Antimicrobial catheters

ABSTRACT

Antimicrobial catheters and medical devices are provided. In some aspects, a low durometer aliphatic polyether polyurethane may be impregnated with a first antimicrobial agent (e.g., minocycline and rifampin) and coated with a second antimicrobial agent (e.g., chlorhexidine, gendine, or gardine). The antimicrobial catheters may display improved flexibility and resistance to kinking. Methods of producing the antimicrobial catheters are also provided.

This application is a continuation of U.S. application Ser. No.16/924,096, filed Jul. 8, 2020, which is a divisional of U.S.application Ser. No. 14/784,747, filed Oct. 15, 2015, which is anational phase application under 35 U.S.C. § 371 of InternationalApplication No. PCT/US2014/034551, filed Apr. 17, 2014, which claims thebenefit of U.S. Provisional Application No. 61/813,542, filed Apr. 18,2013, the entirety of each of which is incorporated herein by reference.

BACKGROUND OF THE INVENTION 1. Field of the Invention

The present invention relates generally to the field of medical devicesand medicine. More particularly, it concerns antimicrobial catheterswith improved antimicrobial and physical properties.

2. Description of Related Art

Vascular catheters are important life saving devices with widespreaduse. They provide direct, immediate access to the bloodstream for avariety of critical purposes including transfusions, administeringmedications, nutrition, blood sampling for testing, and cardiac pressureand output monitoring. Catheters with multiple lumens are often used tomeet these different needs.

Although catheters can provide many benefits, a significant risk ofinfection remains. Because vascular catheters provide access acrosssurfaces that are ordinarily sealed from external environments, they canserve as conduits for pathogenic micro-organisms to colonize cathetersurfaces and gain access to the bloodstream. Potential complicationsinclude bacteremia and bloodstream infection. Catheter associated bloodstream infections can be costly to treat and may also result insignificant adverse effects including mortality. Antimicrobial cathetersincorporate antimicrobial agents to prevent infections. The clinicalbenefits of specific antimicrobial catheters have been shown, andMinocycline/Rifampin and Chlorhexidine/Silver Sulfadiazine cathetershave recently been accorded the highest level recommendation for use bythe Center for Disease Control (CDC) committee on Central LineAssociated Blood Stream Infections (CLABSIs). The organisms causingCLABSIs are consistently shifting in prevalence. Over the last decadethe reported relative incidence of infection by Candidemia,Enterococcal, and gram negative organisms has increased. Accordingly,improved antimicrobial agent combinations are needed to respond to thesenew threats. Chlorhexidine has been combined with Minocycline andRifampin (CH/M/R) to give broader spectrum protection. In otherinstances, the combination of chlorhexidine with triarylmethane dyessuch as Gentian Violet (gendine) or Brilliant Green (gardine) have beenused to provide improved antimicrobial protection.

The improvements in antimicrobial protection associated with CH/M/R andGendine/Gardine combinations have lead to some undesirable complicationsor costs. As shown herein, one such complication is that the processesneeded to incorporate these agents into vascular catheters can result incatheters that can display undesirable mechanical properties. Stiffcatheters are generally required to withstand the solvents andpenetrating agents required for impregnation of the antimicrobialagents. Residual stiffness in the catheters can irritate and inflame theblood vessels they reside within. This irritation is frequently a resultof mechanical stress exerted by the catheter on the vessel wall. If thecatheter is present in a vein, this can lead to phlebitis, stenosis,and/or thrombus formation. Other mechanical complications may also beassociated with the function of catheters. In curved vessels, thebending of stiff or inelastic catheters can kink, causing lumens to sealunder aspiration or have reduced cross-sectional area. As further shownherein, the introduction of several antimicrobial agents in combinationcan also create physical and chemical stability challenges associatedwith long-term storage. Antimicrobial agents may migrate over time tosurfaces creating roughness or rapid release of the antimicrobialagents. Thrombus can also form on the catheter due to thrombin orplatelet activation, which can occlude lumens. Methods involved withimpregnating additional antimicrobial agents can raise the costsassociated with making and packaging antimicrobial catheters toeconomically unattractive levels. Clearly, there remains a need forantimicrobial catheters with improved physical properties.

SUMMARY OF THE INVENTION

The present invention overcomes limitations in the prior art byproviding in some aspects antimicrobial catheters with improvedstrength, stability, and/or flexibility. These improved physicalproperties may be observed over long-term storage of the catheters.Improved methods for producing low durometer antimicrobial polyetherpolyurethanes comprising antimicrobial agents are also provided. Tefloncatheters, canulas, and tubing can be used in a variety of a medicalapplications including, e.g., subdermal infusion of medications frompumps such as insulin. To minimize infection risks associated withcontinuous infusion, manufacturers typically recommend rotatinginsertion sites every 1-3 days. Antimicrobial coatings and catheters asdescribed herein may further reduce infection risk and/or increase thetime between rotations of catheter placement, thereby reducing the costsand inconvenience associated with catheter exchanges.

An aspect of the present invention relates to a medical devicecomprising an aliphatic polyether polyurethane polymer having adurometer of A or B wherein the polyurethane is impregnated withminocycline and rifampin. The aliphatic polyether polyurethane polymermay have a durometer of A. The polyurethane may be coated or impregnatedwith a guanidium compound such as, e.g., chlorhexidine. The coating mayfurther comprise a dye (e.g., gendine or gardine). The coating maycomprise gendine, gardine, or chlorhexidine. The coating may comprisegendine, gardine, and chlorhexidine. The polyurethane may be coated withgendine, gardine, and chlorhexidine. The guanidium compound may bechlorhexidine. The medical device may further comprises a dye (e.g.,gendine or gardine) impregnated into the polyurethane. In someembodiments, the polyurethane is impregnated with gendine, gardine, orchlorhexidine. In some embodiments, the polyurethane is impregnated withgendine, gardine, and chlorhexidine. The coating may comprise or beimpregnated with a lower alcohol. In some embodiments, the polyurethaneis impregnated with or coated with a fatty acid. The fatty acid may becaprylic acid (octanoic acid), caproic acid, lauric acid, or decanoicacid, hexanoic acid, or dodecanoic acid. The aliphatic polyetherpolyurethane polymer may have or comprise a repeating unit of theformula: [—O(CH₂)_(n)]_(m)—OC(O)NH—(CH₂)_(x)—NHC(O)—; wherein n=1-4,x=1-12, and m is 1-100, wherein the repeating unit repeats 1-250 times,and the terminus of the polymer is hydrogen. In some embodiments, therepeating unit is repeated is 1-100, 2-100, 2-50, or 2-10 times. Largerrepeating units may be used in some embodiments; for example, in someembodiments the repeating unit is repeated 100-500 or 100-1000 times. Insome embodiments, m=1-50. In some embodiments, the repeating unit isrepeated 1-100 times. In some embodiments, x=1-10. The polymer mayfurther comprise a polymer coating comprising chlorhexidine, gendine, orgardine. The polymer coating may further comprise a polyurethane, asilicone, a vinyl, a fluoropolymer, an olefin, or a polymer blend orcopolymer thereof. In some embodiments, the polymer coating is apolyurethane coating. The polyurethane coating may be an aliphaticpolyether polyurethane. The polyurethane coating may have a durometer ofA or D, or the coating may comprise a blend of A and D durometeraliphatic polyether polyurethanes. In some embodiments, the aliphaticpolyether polyurethane is comprised in a coating on the medical device.In some embodiments, wherein the aliphatic polyether polyurethane is notcomprised in a coating on the medical device. In some embodiments, themedical device does not comprise a penetrating or alkalizing agent. Insome embodiments, the coating may be prepared with a blend of aliphaticpolyurethane and hydrogel polyetherurethanes (e.g., Tecophilic®). Forexample, coatings may be prepared with blend ratios of about 0:100,1:99, 10:90, 25:75, 50:50, 75:25, 90:10 or 100:0, or any range derivabletherein, and total polyurethane concentrations may range, e.g., fromabout 5 to 11%. As shown in the below examples, blended coatings with10% or more hydrogel polyetherurethane may display improved lubricity.In some embodiments, the coating may comprise Tecoflex® 60D andTecoflex® 93A, optionally comprising an antimicrobial agent (e.g.,chlorhexidine, etc.).

The medical device may be a catheter, an endotracheal tube, anephrostomy tube, a biliary stent, an orthopedic device, a valve, aprosthetic valve, a drainage tube, a drain, a shunt, a staple, a clip, amesh, a film, a blood exchanging device, a port, a cardiovasculardevice, a defibrillator, a pacemaker lead, a wire coating, an ocularimplant, an auditory implant, a cochlear implant, a dental implant, astimulator, a drug delivery depot, a filter, a membrane, a vascularaccess port, a stent, an envelope, a bag, a sleeve, intravenous or othertubing, a bag, a dressing, a patch, a fiber, a pin, a vascular graft, asuture, a cardiovascular suture, or an implantable prosthesis. In someembodiments, the medical device is a catheter such as, e.g., a vascularcatheter, a urinary catheter, an intracranial catheter, an intraspinalcatheter, a peritoneal catheter, a central nervous system catheter, acardiovascular catheter, a drainage catheter, a soaker catheter, anaspirating catheter, an intrathecal catheter, a neural catheter, astimulating catheter, or an epidural catheter. The catheter may be avascular catheter such as, e.g., a central venous catheter, an arterialline, an pulmonary artery catheter, a peripheral venous catheter, anintravenous catheter, or an intraarterial catheter. In some embodiments,a surface of the polyurethane is coated with gendine, gardine, orchlorhexidine in a lower alkyl alcohol solvent. In some embodiments,minocycline and rifampin have been impregnated in the polyurethane usinga solution that does not comprise a penetrating or alkalizing agent. Insome embodiments, the medical device does not comprise a penetrating oralkalizing agent. The polyurethane may further comprise an additionaltherapeutic agent. The additional therapeutic agent may be impregnatedin the polyurethane. In some embodiments, the additional therapeuticagent is coated on a surface of the polyurethane. The therapeutic agentmay be an antimicrobial agent such as, e.g., chlorhexidine, gendine, orgardine. The additional therapeutic agent may be a thrombin inhibitor, aplatelet inhibitor, an anti-inflammatory agent, an anti-fibrotic agents,or a vasodilator. In some embodiments, the additional therapeutic agentis argatroban, dipyridamole, a glyceryl nitrate or mercaptoethanesulfonate (MeSNA). MeSNA may be used to reduce or treat stricture, e.g.,around a catheter. The additional therapeutic agent is calcium channelblocker, or an anti-arrhythmia drug such as, e.g., verapamil orthioridazine. In some embodiments, at least a portion of the medicaldevice is coated with a hydrogel polyetherurethane. The hydrogelpolyetherurethane may be a TECOPHILIC, TECOFLEX, or a polyurethanecopolymer. In some embodiments, the medical device comprisespolytetrafluoroethylene. In some embodiments, a surface of the medicaldevice is coated or the device is impregnated with a chelator. In someembodiments, the chelator is calcium disodium EDTA. In some embodiments,the calcium disodium EDTA is comprised in an amount of about 0.01-1.5%,0.1-1.5%, 0.5-1.5%, or 1-1.5% EDTA in a coating solution. The medicaldevice may be a catheter such as, e.g., a drainage catheter or avascular catheter. In some embodiments, the catheter is impregnated orcoated with chlorhexidine. In some embodiments, the aliphatic polyetherpolyurethane polymer is coated on the surface of the medical device.

Another aspect of the present invention relates to a medical devicecomprising an aliphatic polyether polyurethane polymer having adurometer of A or B wherein the polyurethane is impregnated withchlorhexidine, gendine, or gardine. In some embodiments, the polyetherpolyurethane polymer is coated with a polyurethane coating comprisingminocycline and rifampin. In some embodiments, the aliphatic polyetherpolyurethane is coated with a second polymer. The second polymer may bea polyurethane. In some embodiments, the aliphatic polyurethane isimpregnated with chlorhexidine and gardine. In some embodiments, thealiphatic polyurethane is impregnated with chlorhexidine and gendine. Insome embodiments, the aliphatic polyurethane is impregnated withchlorhexidine, gendine, and gardine. In some embodiments, the secondpolymer comprises minocycline and rifampin. In some embodiments, thepolymer is a polyurethane such as, e.g., an aliphatic polyetherpolyurethane. In some aspects, the medical device may comprise analiphatic polyether polyurethane polymer having a durometer of A or Bwherein the polyurethane is impregnated with minocycline, rifampin,chlorhexidine, gendine, or gardine; wherein the polyurethane is coatedwith a second polyurethane (e.g., wherein the second polyurethanecoating comprises minocycline and rifampin). In some embodiments, thepolyurethane coating has a durometer of A or D, or the coating comprisesa blend of A and D durometer aliphatic polyether-urethanes. The medicaldevice may be a catheter. In some embodiments, the at least a portion ofthe medical device is coated with a hydrogel polyetherurethane. Thehydrogel polyetherurethane may be a TECOPHILIC, TECOFLEX, or apolyurethane copolymer. In some embodiments, a surface of the medicaldevice is coated or impregnated with a chelator such as, e.g., calciumdisodium EDTA. The medical device may be a catheter such as, e.g., adrainage catheter or a vascular catheter. The catheter may beimpregnated or coated with chlorhexidine. In some embodiments, thealiphatic polyether polyurethane polymer is coated on the surface of themedical device.

Yet another aspect of the present invention relates to a medical device,comprising a polymer impregnated with minocycline and rifampin, whereina surface of the polymer is coated with a polymer coating comprising afatty acid or a guanidium compound. The polymer coating may comprise apolyurethane, a silicone, a vinyl, a fluoropolymer, an olephin, or apolymer blend or copolymer thereof. In some embodiments, the polymer ispolytetrafluoroethylene. In some embodiments, the polymer coating is apolyurethane coating. The polyurethane coating may have a durometer of Aor D, or the coating may comprise a blend of A and D durometer aliphaticpolyether-urethanes. The polyurethane may comprise chlorhexidine. Thefatty acid may be caprylic acid (octanoic acid), caproic acid, lauricacid, or decanoic acid. In some embodiments, the fatty acid is capyrlicacid. The polymer coating may further comprises mercaptoethane sulfonate(MeSNA). The medical device may further comprise a thrombin inhibitor, aplatelet inhibitor, an anti-inflammatory agent, an anti-fibrotic agents,or a vasodilator. The polymer may be a polyurethane, a silicone, apolyvinyl chloride (PVC), a fluoropolymer, or a polyester, or acopolymer or blend thereof. The at least a portion of the medical devicemay be coated with a hydrogel polyetherurethane. The hydrogelpolyetherurethane may be a TECOPHILIC, TECOFLEX, or a polyurethanecopolymer. The medical device may comprise polytetrafluoroethylene. Thepolytetrafluoroethylene may be TEFLON. A surface of the medical devicemay be coated or impregnated with a chelator such as, e.g., calciumdisodium EDTA. The medical device may be a catheter such as, e.g., adrainage catheter or a vascular catheter. The catheter may beimpregnated or coated with chlorhexidine. The aliphatic polyetherpolyurethane polymer may be coated on the surface of the medical device.

Another aspect of the present invention relates to an antimicrobialcatheter, wherein the body of the catheter comprises an A durometeraliphatic polyether polyurethane polymer, wherein the polyurethane isimpregnated with (i) minocycline and rifampin or (ii) chlorhexidine,gendine, or gardine. In some embodiments, the catheter is anantimicrobial catheter, wherein the body of the catheter comprises an Adurometer aliphatic polyurethane polymer, wherein the polyurethane isimpregnated with minocycline and rifampin. The aliphatic polyetherpolyurethane polymer may have a repeating unit of the formula:[—O(CH₂)_(n)]_(m)—OC(O)NH—(CH₂)_(x)—NHC(O)—; wherein n=1-4, x=1-10, m isless than 100 or 1-100, and m is greater than x, the repeating unitrepeats 1-250 times, and the terminus of the polymer is hydrogen. Insome embodiments, m is 1-100 or m is 1-50. In some embodiments, therepeating unit repeats 1-100 times. The at least a portion of themedical device is coated with a hydrogel polyetherurethane such as,e.g., a TECOPHILIC or a polyurethane copolymer. In some embodiments, asurface of the medical device is coated or impregnated with a chelator.The chelator may be, e.g., calcium disodium EDTA or a citrate. Thecatheter may be impregnated or coated with chlorhexidine. In someembodiments, the aliphatic polyether polyurethane polymer is coated onthe surface of the medical device.

The polyurethane may further comprise a polymer coating (e.g., apolyurethane, a silicone, a polyvinyl chloride (PVC), a fluoropolymer,or a polyester, or a copolymer or blend thereof) comprising anadditional therapeutic agent. The additional therapeutic agent may be anantimicrobial agent. The antimicrobial agent may be chlorhexidine,gendine, or gardine. The coating may comprise chlorhexidine and gendine.The coating may comprise chlorhexidine and gardine. The antimicrobialagent may be minocycline or rifampin. In some embodiments, the coatingcomprises minocycline and rifampin. The additional therapeutic agent maybe a thrombin inhibitor, a platelet inhibitor, or a vasodilator. In someembodiments, the additional therapeutic agent is argatroban,dipyridamole, a glyceryl nitrate, or a thrombin inhibitor. The cathetermay be a vascular catheter, a urinary catheter, an intracranialcatheter, an intraspinal catheter, or an epidural catheter. In someembodiments, the catheter is a vascular catheter such as, e.g., acentral venous catheter, an arterial line, an pulmonary artery catheter,a peripheral venous catheter, an intravenous catheter, or anintraarterial catheter.

Yet another aspect of the present invention relates to a method ofcatheterization comprising inserting a catheter of the present inventioninto a subject. The subject may be a mammal, such as a human.

Another aspect of the present invention relates to a method of producingan antimicrobial polymer, comprising: (a) contacting an aliphaticpolyether polyurethane with a solution comprising a first lower alcoholand at least one antimicrobial agent for an amount of time sufficient toimpregnate the minocycline and rifampin in the aliphatic polyetherpolyurethane; wherein the solution does not contain a penetrating agentor an alkalizing agent; and (b) substantially drying the aliphaticpolyether polyurethane. In some embodiments, the method of producing anantimicrobial polymer, comprising: (a) contacting an aliphatic polyetherpolyurethane with a solution comprising a first lower alcohol,minocycline, and rifampin for an amount of time sufficient to impregnatethe minocycline and rifampin in the aliphatic polyether polyurethane;wherein the solution does not contain a penetrating agent or analkalizing agent; and (b) substantially drying the aliphatic polyetherpolyurethane. The at least one antimicrobial agent may be minocyclineand rifampin. The at least one antimicrobial agent may be chlorhexidine.The at least one antimicrobial agent may further comprise gendine orgardine. The lower alcohol may be a C₁₋₆ alcohol such as, e.g.,methanol, ethanol, propanol, butanol, or isopropanol. In someembodiments, the solution consists of the lower alcohol. The method mayfurther comprise: (c) subsequent to step (a), coating at least a portionof a surface of the aliphatic polyether polyurethane with a secondsolution comprising: a second lower alcohol, a second organic solvent,and an additional therapeutic compound. The coating may be applied tosubstantially all of the external surfaces of the aliphatic polyetherpolyurethane. The second organic solvent may be an aliphatic ethersolvent or a chlorinated solvent. The chlorinated solvent may bemethylene chloride or chloroform. The aliphatic ether solvent may betetrahydrofuran or diethyl ether. In some embodiments, the second loweralcohol is the same alcohol as the first lower alcohol. The second loweralcohol may be a C₁₋₆ alcohol such as, e.g., methanol, ethanol,propanol, butanol, or isopropanol. In some embodiments, the loweralcohol is methanol. In some embodiments, the solvent is tetrahydrofuranand the second lower alcohol is methanol. In some embodiments, theadditional therapeutic compound is a second antimicrobial agent such as,e.g., minocycline, rifampin, chlorhexidine, gendine, or gardine. Theadditional therapeutic agent may be a thrombin inhibitor, a plateletinhibitor, an anti-inflammatory agent, an antifibrotic agent, or avasodilator. In some embodiments, the additional therapeutic agent isargatroban, or dipyridamole. The additional therapeutic agent may becalcium channel blocker or an anti-arrhythmia drug such as, e.g.,verapamil or thioridazine. In some embodiments, said coating has adurometer of A or D, or the coating comprises a blend of A and Ddurometer aliphatic polyether-urethanes. The aliphatic polyetherpolyurethane may have or comprise a repeating unit of the formula:[—O(CH₂)_(n)]_(m)—OC(O)NH—(CH₂)_(x)—NHC(O)—; wherein n=1-4, x=1-10, m isless than 500, and m is greater than x, the repeating unit repeats 1-250times, and the terminus of the polymer is hydrogen. In some embodiments,m is 1-250 or 1-100. In some embodiments, the repeating unit repeats1-100 times. The resulting polyether polyurethane may have a durometerof A or B. The aliphatic polyether urethane polymer may be comprised ina medical device or a catheter.

In some embodiments, the aliphatic polyether urethane polymer iscomprised in an endotracheal tube, a vascular catheter, a urinarycatheter, a nephrostomy tube, a biliary stent, a peritoneal catheter, anepidural catheter, a central nervous system catheter, an intracranialcatheter, an intraspinal catheter, an epidural catheter, an orthopedicdevice, a prosthetic valve, or a medical implant. The catheter may be avascular catheter such as, e.g., a central venous catheter, an arterialline, a pulmonary artery catheter, and a peripheral venous catheter, anintraarterial catheter, or intravenous (i.v.) tubing.

Yet another aspect of the present invention relates to a method ofproducing an antimicrobial polymer, comprising: (a) contacting a polymerwith a solution comprising a lower alcohol, minocycline, rifampin, andan alkalizing agent for an amount of time sufficient to impregnate theminocycline and rifampin in the aliphatic polyether polyurethane; (b)exposing the polymer to a neutralizing solution comprising an alkanoicacid for an amount of time sufficient to substantially neutralize thealkalizing agent; and (c) substantially drying the polymer. Thealkalizing agent may be sodium hydroxide. The solution may furtherinclude a penetrating agent such as, e.g., ethyl acetate or butylacetate. The polymer may be a polyurethane such as, e.g., an aliphaticpolyether polyurethane. In some embodiments, step (b) comprisesneutralizing a majority or substantially all of the alkylating agent.The lower alcohol may be methanol. The alkanoic acid may be a C₁₋₆alkanoic acid such as, e.g., acetic acid, formic acid, propionic orbutyric acid. In some embodiments, the C₁₋₆ alkanoic acid is aceticacid. The method may further comprise (d) subsequent to step (a),coating at least a portion of a surface of the aliphatic polyetherpolyurethane with a second solution comprising: a second lower alcohol,a second organic solvent, and an additional therapeutic compound. Thecoating may be applied to substantially all of the external surfaces ofthe aliphatic polyether polyurethane. The second organic solvent may bean aliphatic ether solvent or a chlorinated solvent. The chlorinatedsolvent may be methylene chloride or chloroform. The aliphatic ethersolvent may be tetrahydrofuran or diethyl ether. In some embodiments,the second lower alcohol is the same alcohol as the first lower alcohol.In some embodiments, the second lower alcohol is methanol. In someembodiments, the solvent is tetrahydrofuran and the second lower alcoholis methanol. The additional therapeutic compound is an antimicrobialagent such as, e.g., chlorhexidine, gendine, or gardine. The additionaltherapeutic agent may be a thrombin inhibitor, a platelet inhibitor, ananti-inflammatory agent, an antifibrotic agent, or a vasodilator. Insome embodiments, the additional therapeutic agent is argatroban, ordipyridamole. The additional therapeutic agent is calcium channelblocker or an anti-arrhythmia drug such as, e.g., verapamil orthioridazine. The coating may have a durometer of A or D, or the coatingmay comprise a blend of A and D durometer aliphatic polyether-urethanes.The aliphatic polyether urethane polymer may be comprised in a medicaldevice or a catheter. In some embodiments, the polymer is comprised inan endotracheal tube, a vascular catheter, a urinary catheter, anephrostomy tube, a biliary stent, a peritoneal catheter, an epiduralcatheter, a central nervous system catheter, an intracranial catheter,an intraspinal catheter, an epidural catheter, an orthopedic device, aprosthetic valve, or a medical implant. The catheter may be a vascularcatheter such as, e.g., a central venous catheter, an arterial line, apulmonary artery catheter, and a peripheral venous catheter, anintraarterial catheter, or intravenous (i.v.) tubing.

Another aspect of the present invention relates to a catheter comprisinga polymer tubing, wherein the polymer tubing is an aliphatic polyetherpolyurethane polymer, a polyurethane polymer coated with an aliphaticpolyether polyurethane polymer, or a polytetrafluoroethylene polymercoated with an aliphatic polyether polyurethane polymer; wherein thepolymer is coated or impregnated with chlorhexidine, gendine, gardine,minocycline, and/or rifampin. The catheter may further comprise a secondpolymer coating on the polymer tubing. The second polymer coating maycomprise an aliphatic polyether polyurethane. The coating may comprisechlorhexidine, gendine, gardine, minocycline, and/or rifampin. In someembodiments The catheter may further comprise an additional therapeuticagent.

The low durometer polyether polyurethanes as described herein may beincluded on a surface of a medical device or may comprise a medicaldevice such as a catheter. Exemplary medical devices include, e.g., anendotracheal tube, a vascular catheter, a urinary catheter, anephrostomy tube, a biliary stent, a peritoneal catheter, an epiduralcatheter, a central nervous system catheter, an orthopedic device, aprosthetic valve, and a medical implant. The vascular catheter may be acentral venous catheter, an arterial line, a pulmonary artery catheter,or a peripheral venous catheter. The central nervous system catheter maybe an intraventricular shunt. Other medical devices that can benefitfrom the present invention include blood exchanging devices, vascularaccess ports, cardiovascular catheters, extracorporeal circuits, stents,implantable prostheses, vascular grafts, pumps, heart valves, andcardiovascular sutures, to name a few. The medical device may be aprotection article such as a glove, mask, respirator, patch, foot cover,shoe liner, flip flop, ear plug, or nose plug. The medical device may bea structural implant such as penile implant, a cosmetic restorative orenhancement implant such as, e.g., a breast implant. In someembodiments, the medical device is a drainage tube or catheter, a shunt,a staple, a cord, a clip, a mesh, or a film.

In some aspects of the present disclosure, the medical device isprepared using an aliphatic polyether polyurethane polymer, apolyurethane polymer, or a polytetrafluoroethylene polymer. In someembodiments, any of the polymers are coated or impregnated with one ormore therapeutic agent as described in this disclosure. Such therapeuticagents may include, but are not limited to, minocycline, rifampin,chlorhexidine, gendine, gardine, a fatty acid, another antimicrobialagent, a thrombin inhibitor, a platelet inhibitor, an anti-inflammatoryagent, an anti-fibrotic agent, a vasodilator, a calcium channel blocker,an anti-arrhythmia agent, or a metal ion chelator. In some embodiments,the polymer is impregnated or coated with one, two, three, four, five,or six individual agents. In some specific embodiments, the polymer iscoated with minocycline, rifampin, and chlorhexidine, gendine, orgardine. In some embodiments, the polymer is coated or impregnated withminocycline, rifampin, another therapeutic agent, and chlorhexidine,gendine, or gardine. In some embodiments, the polymer is coated withminocycline, rifampin, and another therapeutic agent. In someembodiments, the polymer is coated with chlorhexidine, gendine orgardine and another therapeutic agent. Additionally, in some aspects,the polymer is coated with a second polymer selected from an aliphaticpolyether polyurethane polymer, a polyurethane polymer, or apolytetrafluoroethylene polymer before or after the polymer has beenimpregnated or coated with the above therapeutic agents. In someembodiments, the polymer is coated with a silicone, a vinyl, afluoropolymer, an olefin, or blend of polymers thereof. The secondpolymer coating may itself be impregnated or coated with any of theabove described therapeutic agents. In some embodiments, if the firstpolymer is polytetrafluoropolyethylene, then the polymer can be etchedbefore being coated with a second polymer or coated or impregnated witha therapeutic compound.

The type of nosocomial infection that can be reduced or prevented invarious embodiments include, but are not limited to, pneumonia,bacteremia, fungimia, candidemia, a urinary tract infection, acatheter-exit site infection, and a surgical wound infection. Nosocomialinfections that can be reduced or substantially prevented may be causedby bacteria such as, e.g., drug resistant bacteria. Some non-limitingexample of drug resistant bacteria include methicillin-resistantstaphylococcus, vancomycin-resistant enterococcus, and resistantPseudomonas aeruginosa. The nosocomial infection may be caused by afungus such as, e.g., a drug resistant fungi. Examples of a drugresistant fungi include members of the Candida genus. Infection by otherpathogenic organisms that can cause the nosocomial infections may bereduced or prevented by use of the methods and medical devices, such ascatheters, as described herein.

In various aspects, the antimicrobial agents may reduce the growth of awide variety of bacterial and fungal organisms. The bacteria may bespherical, rod-shaped, or spiral bacteria. Non-limiting examples ofbacteria include staphylococci (e.g., Staphylococcus epidermidis,Staphylococcus aureus), Enterrococcus faecalis, Pseudomonas aeruginosa,Escherichia coli, among other gram-positive bacteria and gram-negativebacilli. Non-limiting examples of fungal organisms include Candidaalbicans and Candida krusei.

The term “organic solvent” as used herein refers to a solvent that canbe used to dissolve antimicrobial agents. Organic solvents includealcohols (e.g., methanol, ethanol), ketones (e.g., acetone,methylethylketone), ethers (e.g., tetrahydrofuran), aldehydes (e.g.,formaldehyde), acetonitrile, acetic acid, methylene chloride andchloroform.

The term “penetrating agent” as used herein refers to an agent ororganic compound that is capable of promoting penetration of anantimicrobial agent, such as a guanidium compound, into the matrix of apolymer, such as a polyurethane, that may be present in or comprise amedical device. Non-limiting examples of such compounds are esters(e.g., ethyl acetate, propyl acetate, butyl acetate, amyl acetate, andcombinations thereof), ketones (e.g., acetone and methylethylketone),methylene chloride and chloroform.

The term “alkalinizing agent” as used herein refers to organic andinorganic bases such as sodium hydroxide, potassium hydroxide, ammoniain water (e.g., 27% ammonium hydroxide), diethylamine and triethylamine.

A “repeat unit” is the simplest structural entity of certain materials,for example, frameworks and/or polymers, whether organic, inorganic ormetal-organic. In the case of a polymer chain, repeat units are linkedtogether successively along the chain, like the beads of a necklace. Forexample, in polyethylene, —[—CH₂CH₂-]_(n)—, the repeat unit is —CH₂CH₂—.In some embodiments of a repeating unit, the ends of the chains arecapped with hydrogens. The subscript “n” denotes the degree ofpolymerization, that is, the number of repeat units linked together.When the value for “n” is left undefined or where “n” is absent, itsimply designates repetition of the formula within the brackets as wellas the polymeric nature of the material. In such a case, the polymer maycontain one or more than one repeating units. The concept of a repeatunit applies equally to where the connectivity between the repeat unitsextends three dimensionally, such as in modified polymers, thermosettingpolymers, etc.

As used herein the specification, “a” or “an” may mean one or more. Asused herein in the claim(s), when used in conjunction with the word“comprising”, the words “a” or “an” may mean one or more than one.

The use of the term “or” in the claims is used to mean “and/or” unlessexplicitly indicated to refer to alternatives only or the alternativesare mutually exclusive, although the disclosure supports a definitionthat refers to only alternatives and “and/or.” As used herein “another”may mean at least a second or more.

Throughout this application, the term “about” is used to indicate that avalue includes the inherent variation of error for the device, themethod being employed to determine the value, or the variation thatexists among the study subjects.

Other objects, features and advantages of the present invention willbecome apparent from the following detailed description. It should beunderstood, however, that the detailed description and the specificexamples, while indicating preferred embodiments of the invention, aregiven by way of illustration only, since various changes andmodifications within the spirit and scope of the invention will becomeapparent to those skilled in the art from this detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS

The following drawings form part of the present specification and areincluded to further demonstrate certain aspects of the presentinvention. The invention may be better understood by reference to one ormore of these drawings in combination with the detailed description ofspecific embodiments presented herein.

FIG. 1 : Plot of Reduction in Adherent Acinetobacter baumanii (cfu/ml)to different polyurethane substrates Impregnated with M/R using onlysolvent and without penetrating or alkalizing agents.

FIG. 2 : Plot of Acinetobacter baumanii colonization on a control,catheter treated by methods in U.S. Pat. Nos. 5,624,704 and 5,902,283,and the current method (60 minutes in methanol).

FIG. 3 : Antimicrobial durability of different catheter treatments.

FIG. 4 : Antimicrobial durability of Gendine sandwich coating againstMRSA.

FIG. 5 : Antimicrobial durability of Gendine sandwich coating againstCandida species.

FIG. 6 : Antimicrobial durability of Gendine sandwich coated Teflon®catheters against MRSA, Staphylococcus epidermidis (SE), and Candida(CA).

FIG. 7 : Antimicrobial durability of catheters against MRSA, Pseudomonasaeruginosa (PS), and Candida albicans (Ca).

FIG. 8 : Inhibition of MRSA colonization by catheter coatings.

FIG. 9 : Antimicrobial durability of catheters containing against MRSA,Pseudomonas aeruginosa (PS), and Candida albicans (Ca).

FIG. 10 : Antimicrobial durability of drainage catheters against MRSA,PS, and Ca.

DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

Provided herein are medical devices and catheters comprisingantimicrobial aliphatic polyether polyurethanes of durometer A or B. Thealiphatic polyether urethane polymer may have a repeating unit of theformula: [—O(CH₂)_(n)]_(m)—OC(O)NH—(CH₂)_(x)—NHC(O)—; wherein n=1-4,x=1-12, and m is 1-100. In some embodiments, it has been observed thatthe polyurethanes may be impregnated and/or coated with antimicrobialagents without adversely affecting the flexibility of the resultingpolymer. These antimicrobial polymers may be particularly useful incatheters, where flexibility and resistance to kinking or breakage isadvantageous for clinical use.

The aliphatic polyether polyurethane polymer may be impregnated with oneor more antimicrobial agents, such as minocycline and rifampin. In someembodiments, the polymer is coated with a polyurethane coatingcomprising an additional antimicrobial agent. The additionalantimicrobial agent may be chlorhexidine, gendine, or gardine. As shownin the below examples, it has been observed that the impregnation of apolymer with minocycline, rifampin, and one of either: chlorhexidine,gendine, or gardine, can adversely affect the flexibility of the polymerover long-term storage. In contrast and as shown in the below examples,separating these antimicrobial agents in different layers of the polymer(e.g., impregnating minocycline and rifampin in the polymer and applyinga separate coating containing chlorhexidine, gendine, or gardine) canresult in antimicrobial polymers that display improved flexibility,mechanical properties, and resistance to kinking during longer-termstorage.

Methods of producing antimicrobial aliphatic polyether polyurethanes arealso provided. In some embodiments, an aliphatic polyether polyurethanemay be impregnated with one or more antimicrobial agents by contactingthe polyurethane with a solution comprising a lower alcohol and theantimicrobial agent(s), wherein the solution does not comprise apenetrating agent or an alkalizing agent. Exclusion of penetratingagents and alkalizing agents may in some embodiments promote retentionof strength and flexibility of the polymer during longer term storage,e.g., over a period of weeks or months. In some embodiments, if it isdesired to use an alkalizing agent, such as sodium hydroxide, to promoteimpregnation of an antimicrobial agent into a polymer, then the methodmay further comprise neutralizing the alkalizing agent. For example,after exposure to an alkalizing agent such as sodium hydroxide, theresulting polymer may be contacted with a solution of acetic acid toneutralize a majority of, or substantially all of, the sodium hydroxidethat remains impregnated in the polymer. Neutralization of any remainingimpregnated alkalizing agent in the polyurethane may also contribute toimproved strength, flexibility, and resistance to kinking and/orbreakage over longer term storage. As shown below in the examples, incontrast to methods which require heating to promote impregnation of anantimicrobial agent in a polymer, it has been observed that thepolyether polyurethanes may be impregnated with an antimicrobial agentin a lower alcohol such as methanol at room temperature. Impregnating anantimicrobial at room temperature (e.g., 25-30° C.) without applyingadditional heating to the polymer may in some embodiments result inimprovements to the strength and flexibility of the resulting polymer.Such improvements to the strength, flexibility, and resistance tokinking of the polymers may be beneficial for the clinical use of thepolymers in medical devices such as catheters.

I. Aliphatic Polyether Urethanes

In some aspects, an aliphatic polyether polyurethane (also referred toherein as an “aliphatic polyether urethane polymer”) may be included ina medical device such as a catheter. Sample chemical structures of thetypes of different polyurethanes are depicted below:

In some embodiments, n=1-4, x=1-12 and m is 1-100. In some embodiments,m is greater than x. n may be 1, 2, 3, or 4. x may be 1-6 or 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11, or 12. In some embodiments, x=1-12, 1-10, 1-8, or1-6. In some embodiments n=4 and x=6. Low durometer (softer) aliphaticpolyurethane typically have a higher fraction of soft segments (m>x) andthe high durometer polyurethanes have a higher proportion of hardsegments (x>m). In some embodiments m=1-100,1-99, 1-90, 1-80, 1-70,1-60, 1-50, 1-40, 1-30, 1-20, or any range derivable therein. In someembodiments, the polymer has the formulaH[—O(CH₂)_(n)]_(m)OC(O)NH—(CH₂)_(x)—NHC(O)—H. In some embodiments, thealiphatic polyether polyurethane is a low durometer polyurethane.

On the other hand, a typical aromatic polyether urethane chemicalstructure is depicted below:

where, unlike in the aliphatic polyurethanes, the hard segments containaromatic groups. Modifications of the exact chemical structure of thesoft and hard segments from the sample structure above are possible. Thedurometer of the given polyurethane is governed by the relativeproportion of soft and rigid segments.

As used herein, a “polyether polyurethane”, “polyether urethane”, or“polyether-urethane” may refer to an aliphatic polyether polyurethane,as described above.

A variety of copolymers or blends may be used with the presentinvention. In some embodiments, a polyurethane may be blended withanother polymer. In some embodiments, minocycline and rifampin areimpregnated into a polymer, copolymer, or polymer blend present in amedical device. These polymers, copolymers, and polymer blends includepolyurethanes, polyvinylchlorides, silicones, polyesters, polyolephinsand fluoropolymers. In some embodiments the polyurethane is apellethane. In some embodiments, the polymer, copolymer, or blend isimpregnated with minocycline and rifampin and then one or more of thesurfaces of the polymer, copolymer, or blend is coated withchlorhexidine. The coating may comprise a co-dissolved polymer. Thepolymer may be a polyurethane. As described in further detail herein,the coating may be generated by exposing the polymer to a solvent, e.g.,containing an additional therapeutic agent. Upon evaporation of thesolvent, the polyurethane can dry to an adherent elastic coating. Anuncured silicone can also be included in a coating. Subsequent to beingapplied, an uncured silicone may cure in situ to form an adherentelastic coating.

In some embodiments, the aliphatic polyether polyurethanes which can beformulated into a medical device include Lubrizol Tecoflex™ EG80A,EG85A, EG93A or EG100A, Bayer Duraflex® A4700 aliphatic ether TPU,Argotec® Argothane Aliphatic Polyether TPU 3751, or AdvanSourceBiomaterials HydroSlip™ Hydrophilic Polyether Aliphatic Polyurethane. Insome embodiments, Lubrizol Tecoflex™ EG93A can be formulated into amedical device. It is anticipated that a polyester including apolycaprolactone based polyurethane elastomer may be used instead of, orin combination with, a polyether polyurethane. The polyester basedpolyurethane elastomer may be an Estane™ In various embodiments, one ormore of the following commercially available materials may be blended orotherwise used in various embodiments: Texin™, Desmopan™ (Bayer,Leverkusen, Germany); ChronoThane™, ChronoFlex™, HydroMed™ HydroThane™(Advanced Biomaterials, Wilmington, MA); Quadrathane™, Quadraflex™Quadraphilic™ (Biomerics, Salt Lake City, UT). Polyurethanes of thecurrent invention may also contain carbonate blocks, siloxane blocks, orsilane derivatives.

A. Durometer and Polyurethane Hardness Scales

One property that reflects different polyurethane stiffness that arisesfrom different monomer chemistries is durometer. Durometer measurementis defined in ASTM-D2240 and is a measure of material hardness throughthe depth of indentation generated by a given applied force using aspecific tip geometry. Within the durometer system, there are numerousdifferent scales used for different materials with different properties.Durometers measured on the A scale (for softer plastics) utilize atruncated conical tip and durometers measured on the D scale use apointed conical tip. Durometer types A-D are traditionally used todenote the hardness of plastics with types A and D being the mostlycommonly used. Type A refers to soft rubbers and plastics which caneasily deform while type D is used to describe harder plastics, e.g.,used to make bowling balls and hard hats. Within each type, the materialis given a numeric subscore from 1-100 with 100 being the hardestmaterial of that type and 1 being the softest. While the system hasnumerous different scales as outlined by the standard, the scalesoverlap so that a material with a type A 100 score would correlate witha type D score of 58. In some embodiments of the present invention, thehardness of the materials used to construct the medical device is typeA-D durometer with a type A score of between 30 and 100. In someembodiments, the material has a hardness scored as a type A 93. In someembodiments, a polyether polyurethane, as described herein, has adurometer of A or B. In some embodiments, polyurethane is a lowdurometer or an A durometer polyurethane. The durometer polyurethane maybe from 30A to 80D. In some preferred embodiments, the durometer of thepolyurethane is from 80A to 95A.

B. Therapeutic Agents

A medical device, such as a catheter, may be impregnated or coated withone or more therapeutic agents. For example, the medical device orcatheter may contain one or more antimicrobial agents, such as rifampinand minocycline, to help to decrease the incident of infections andadverse events. In some embodiments, the antimicrobial agents areincorporated into a surface of the medical device or catheter throughimpregnation of the polyether polyurethane. The therapeutic agent may bepresent in a coating or coated on the polymer surface.

In some embodiments, the polyether polyurethane surface or body of themedical device or catheter is impregnated with minocycline and rifampin.Rifampin is a bactericidal antibiotic drug of the rifamycin group. TheIUPAC systematic name for rifampin is(7S,9E,11S,12R,13S,14R,15R,16R,17S,18S,19E,21Z)-2,15,17,27,29-pentahydroxy-11-methoxy-3,7,12,14,16,18,22-heptamethyl-26-{(E)-[(4-methylpiperazin-1-yl)imino]methyl}-6,23-dioxo-8,30-dioxa-24-azatetracyclo[23.3.1.14,7.05,28]triaconta-1(28),2,4,9,19,21,25(29),26-octaen-13-ylacetate. Minocycline may also be incorporated into the polyetherpolyurethane surface or body of the device. Minocycline is a broadspectrum tetracycline based antibiotic with an IUPAC systematic name of(2E,4S,4aR,5aS,12aR)-2-(amino-hydroxy-methylidene)-4,7-bis(dimethylamino)-10,11,12a-trihydroxy-4a,5,5a,6-tetrahydro-4H-tetracene-1,3,12-trione.

The polyether polyurethane surface or catheter be impregnated withchlorhexidine. Chlorhexidine(N′,N′″″-hexane-1,6-diylbis[N-(4-chlorophenyl)(imidodicarbonimidicdiamide)]) is a small molecule antiseptic which can be effective againstGram-positive as well as Gram-negative bacteria. In some embodiments,chlorhexidine may be used in combination with, or may be substitutedwith, another antimicrobial guanidium compound such as, e.g., alexidine,hexamidine, polyhexamethylbiguanide or a chlorhexidine salt.

In some embodiments, a polyurethane polymer or catheter may be coated orimpregnated with gendine or gardine. Gendine is a combination of bothchlorhexidine and the dye, Gentian violet. Gentian violet is atriarylmethane dye which is good at impregnating different types ofpolymers. Additionally, other dyes, such as Brilliant Green and foodsafe dyes such FD&C Blue No. 1 and FD&C Yellow No. 5. When BrilliantGreen is combined with chlorhexidine, the combination is called Gardine.These mixtures of dyes and chlorhexidine cause each compound to betterimpregnate the polymer leading to greater antibiotic efficiency and workwith a wide range of different polymer formulations. A range of ratiosof chlorhexidine to dye may be used, e.g., as described in U.S. Pat. No.7,713,472.

A medium chain fatty acids or monoglyceride may be impregnated in orcoated on a polymer as disclosed herein. The medium chain fatty acids ormonoglyceride may have broad spectrum antimicrobial activity. Exemplarymedium chain fatty acids that may be used include hexanoic, octanoic,decanoic and dodecanoic acids and their monoglycerides. The fatty acidmay be a C₆₋₁₂ alkanoic acid or a C₆₋₁₀ alkanoic acid. Without wishingto be bound by any theory, the medium chain fatty acid or monoglyceridemay enhance membrane permeability or otherwise disrupt membrane functionin a microorganism such as a bacteria. The medium chain fatty acid ormonoglyceride may be combined with one or more antibiotics such as,e.g., minocycline and rifampin. The fatty acid or monoglyceride may beincorporated into an emulsion, suspension, or solution in a polymericcoating as described herein. In some embodiments, the medium chain fattyacid or monoglyceride is applied onto one or more surfaces of a polymer,such as an aliphatic polyether polyurethane, that is impregnated withminocycline and rifampin.

In some embodiments, the polyether polyurethane surface or cathetercomprises an anticoagulant, a platelet inhibitor, or a direct thrombininhibitor. Impregnation of an anticoagulant in a catheter may reduce theprobability of the catheter becoming clogged or occluded. Reducing theprobability of catheter occlusion may be particularly desirable inembodiments where the catheter may be used intraarterially orintravenously. In some embodiments, agratoban is included on orimpregnated in the polyether polyurethane surface or body. Argatroban isan anticoagulant with the IUPAC systematic name of(2R,4R)-1-[(2S)-5-(diaminomethylideneamino)-2-[[(3R)-3-methyl-1,2,3,4-tetrahydroquinolin-8-yl]sulfonylamino]pentanoyl]-4-methyl-piperidine-2-carboxylicacid]]. In some embodiments, dipyridamole may be included on or in thepolyether polyurethane surface or body. Dipyridamole(2,2′,2″,2′″-(4,8-di(piperidin-1-yl)pyrimido[5,4-d]pyrimidine-2,6-diyl)bis(azanetriyl)tetraethanol)can inhibit thrombus formation and promote vasodilation. In someembodiments a glycerol nitrate may be included on or in the polyetherpolyurethane surface or body. Glycerol nitrates can inhibit plateletactivation (e.g., He'bert et al., 1997, Lacoste et al., 1994).

In some embodiments, the polyether polyurethane surface or catheter maycontain a calcium channel blocker. Calcium channel blockers may increasethe supply of blood and oxygen to the heart, and inclusion of a calciumchannel blocker may be useful, e.g., for inclusion in catheters that maybe used intraarterially or intravenously. The calcium channel blockermay be verapamil, amlodipine, nifedipine, diltiazem, thioridazine, or athioridazine analogue. In some embodiments, the calcium channel blockeris a phenylalkylamine class L-type calcium channel blocker, such as,e.g., verapamil((RS)-2-(3,4-dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl]-(methyl)amino}-2-prop-2-ylpentanenitrile]])or thioridazine(10-{2-[(RS)-1-Methylpiperidin-2-yl]ethyl}-2-methylsulfanylphenothiazine]]).It is anticipated that a wide variety of therapeutic agents may beincluded in a catheter of the present invention. In some embodiments,the calcium channel blocker is impregnated in or coated on the aliphaticpolyether polyurethane.

II. Methods for Producing Catheters and Polyurethane Surfaces

A. Alkalizing Agents and Penetrating Agents

In some aspects, a polymer present in a medical device may beimpregnated with one or more therapeutic agents without the use of analkalizing agent or a penetrating agent. In some embodiments, thepolymer is a low durometer polyether polyurethane present in a medicaldevice such as a catheter. As described in further detail below in theExamples, the inventors have observed that use of a penetrating agent oran alkalizing agent can adversely affect the flexibility, strength,and/or susceptibility to kinking of a catheter. Catheters with reducedflexibility may have an increased likelihood of kinking and may be lesssuitable for clinical use. As described below, exposure of apolyurethane, such as a polyether polyurethane, to a solution comprisinga lower alcohol (e.g., methanol) and one or more antimicrobial agents(e.g., minocycline and rifampin) can allow for impregnation of theantimicrobial agents into the polyurethane without the use of analkylating agent or a penetrating agent.

Generally, an alkalizing agent can modify the bulk pH of the material byraising the pH. Alkalizing agents include hydroxide bases such as sodiumhydroxide. A penetrating agent is an organic molecule which can be usedto increase the polymers permeability, and may be used to enhance theability of the molecules being added to the polyurethane to impregnatethe polymer. Penetrating agents for the polyurethanes include nonpolaragents such as, e.g., ethyl or butyl acetate. Additional alkylatingagents are described, e.g., in U.S. Pat. Nos. 5,624,704 and 5,902,283,which are incorporated herein by reference in their entirety.

Impregnation of an antimicrobial agent into an aliphatic polyetherpolyurethane may be accomplished by exposing the polyurethane to asolution comprising a lower alcohol, wherein the solution does notcomprise a penetrating agent or an alkalizing agent. In someembodiments, the impregnation of one or more antimicrobial agents into apolyether polyurethane can be accomplished by exposing the polyetherpolyurethane to a solvent, such as a lower alcohol solvent (e.g.,methanol, ethanol, butanol, isopropanol) comprising the antimicrobialagents (e.g., minocycline and rifampin) for about 1-600 minutes, 1-60minutes, 1-30 minutes, 1-15 minutes, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, or 15 minutes or any derivable range therein.

The impregnation reaction may be carried out at room temperature. Insome embodiments, a low durometer polyether polyurethane may beimpregnated with antimicrobial agent(s), such as minocycline andrifampin, in a lower alcohol solvent at room temperature. Theimpregnation reaction may occur at about 25-30° C., or 25, 26, 27, 28,29, or 30° C., or any derivable range therein. Although in someembodiments, impregnation occurs at room temperature, it is nonethelessanticipated that a wider range of temperatures may be used, if desired.For example, the impregnation of antiseptic compounds and mixtures mayoccur at a temperature between about 25-50° C. After the impregnation ofone or more antiseptics or antimicrobial agents, the polyurethanepolymer may be more resistant to the colonization of bacteria such asPseudomonas aeruginosa, e.g., as shown in the below examples.

B. Neutralization Method for Producing Catheters with Reduced Kinking

In some aspects, if it is desired to use an alkalizing agent to promoteimpregnation of an antimicrobial agent into a polymer, the method mayfurther comprise a neutralization step to substantially neutralize amajority or substantially all of the alkalizing agent that may remainimpregnated in the polymer. In some embodiments, inclusion of aneutralization step may be used to produce catheters with improvedstrength, flexibility, and/or resistance to kinking.

Although alkalinizing agents can increase impregnation of anantimicrobial agent, they may also reduce the strength and flexibilityof the resulting polymer. For example, alkaline process aids such assodium hydroxide can affect polyurethane catheter durability such that astiff starting catheter composition is generally required to obtain afinal catheter with sufficient mechanical strength. The use of a stiffstarting catheter can make it more prone to kink upon flexure. As shownin the below examples, adding an acid neutralizing step followingimpregnation of antimicrobial agents (e.g., minocycline, rifampin,and/or chlorhexidine) may be used to promote neutralization of anyresidual alkalinizing agent in the catheter or medical device. In someembodiments, the neutralization step comprises washing the polyurethanein a solution comprising about 0.5-3% acetic acid.

Methods for using an organic solvent and a penetrating agent toimpregnate polymeric devices with antimicrobial compositions, such asminocycline and rifampin, are described in U.S. Pat. Nos. 5,624,704 and5,902,283, which are incorporated by reference herein in their entirety.An alkalinizing agent may be used to substantially enhance the extent ofimpregnation. The inventors have observed that when alkalizing agentsare used with elastomeric polymer devices such as, e.g., a polyetherpolyurethane catheters, the incorporation of an acid neutralizing step,post-alkalinization, can substantially enhance the elasticity and reducethe stiffness of the resulting antimicrobial polyurethane device. Insome embodiments, the alkalizing agent is sodium hydroxide, and theneutralization step comprises exposing the polymer to a solution ofacetic acid for an amount of time sufficient to neutralize a majority ofor substantially all of the impregnated sodium hydroxide.

In some embodiments, the following neutralization method may be used. Apolyurethane catheter may be incubated at about 45° C. in a solutioncontaining about 15% methanol/85% butyl acetate solution that furthercomprises one or more antimicrobial agents, such as minocycline andrifampin, and about 1% sodium hydroxide. After a 1 hour treatment, thecatheter segments may be air flushed and then dried overnight at 60° C.The dried catheters may be washed repeatedly, e.g., triple washed, indeionized water containing 1% acetic acid. Th catheter may then be driedagain, e.g., for 4 hours at 60° C. Washing with a solution comprising aneutralizing agent may be performed for about from about 1 minute to 24hours, from 1 minute to 1 hour, or about 1-15 minutes.

C. Sandwich Design for M/R/CH and Gendine/Gardine Catheters withImproved Kink Resistance and Stability:

As shown in the below examples, the combination of minocycline,rifampin, and chlorhexidine (M/R/CH) impregnated in catheters wereobserved by the inventors to display reduced stability over longerperiods of storage. Without wishing to be bound by any theory, theseresults support the idea that this particular combination of compoundscan, when simultaneously impregnated in a catheter or polymer, interactwith the polymer to adversely affect the physical characteristics of thepolymer. The inventors have observed that when these three componentsare simultaneously co-impregnated in a catheter (e.g., using the methodof presaturating the catheter with chlorhexidine (CH) followed byimpregnating with minocycline (M) and rifampin (R), as described inUS20120064372) that over the course of several months storage at 25° C.,a dull powdery substance can form along the surface. This formation istypically undesirable as it may impede insertion of the catheter andcould serve as a source for thrombus formation.

In some embodiments, a polymer coating, optionally containing M, R or CHon both the lumenal and external surfaces, can reduce or substantiallyprevent migrating antimicrobial agents from reaching the surface. Apolyurethane coating has been found to be the optimal coating for apolyurethane catheter and that a polyether urethane can be dissolved involatile solvents and can be applied as a solution. Surprisingly, theexternal coating in conjunction with M/R/CH or Gendine/Gardine,particularly when comprising a blend of D and A durometer aliphaticpolyether-urethanes, enhances kink resistance and elasticity.

In some embodiments, an aliphatic polyether polyurethane in a medicaldevice, such as a catheter, as described herein may be impregnated withgendine, gardine, or chlorhexidine and coated with M and/or R. It isanticipated that a similar enhancements to kink resistance andelasticity may be observed in such catheters as compared to cathetersimpregnated with M and R and coated with gendine, gardine, orchlorhexidine. The coating may comprise A or D durometer aliphaticpolyether-urethanes or a blend of D and A durometer aliphaticpolyether-urethanes.

D. Simplified Method for Impregnating Aliphatic Polyether-Urethanes withM/R/CH or Gendine/Gardine

Impregnating stiffer polyurethanes with M/R and optionally CH currentlyinvolves the use of a solvent, penetrating agent and preferably analkalinizing agent. The process may take over 1 hour to complete. Usingspecific soft polyurethanes, the current invention provides in variousaspects methods for producing catheters while omitting penetrating andalkalinizing agents. In some embodiments, an A durometer aliphaticpolyether-urethanes may be impregnated with antimicrobial agents (e.g.,M/R/CH, Gendine/Gardine, CH, or M/R) using only a solvent, such as alower alcohol. Furthermore, the impregnation of these polymers can beaccomplished in less than about 5 minutes. In some embodiments, theimpregnation can be achieved in 1, 2, 3, 4 or 5 minutes or any rangederivable thereof. In some embodiments, the impregnation can occur atroom temperature. In some embodiments, the impregnation occurs at atemperature can be between 25 and 30° C. In some embodiments, theimpregnation occurs at a temperature of 25, 26, 27, 28, 29 or 30° C., orany range derivable thereof. Because these methods may reduces theproduction time, the cost effectiveness of the catheter production mayalso be improved. Increasing the impregnation temperature can furtherreduce the time required for impregnation. The ability to exclude apenetrating and alkalinizing agent may reduce supply chain complexity,material and waste disposal costs, and processing costs.

Impregnating an A-durometer aliphatic polyether polyurethane with one ormore antimicrobial agents (e.g., M/R/CH) may be accomplished usingthermodynamically favorable mixing with the polymer and a solvent (e.g.,a lower alcohol) containing the antimicrobial agent(s), without theinclusion of any penetrating agents, alkalinizing agents, orpermeabilizing agents (e.g., sodium hydroxide) in the solvent. Aliphaticpolyether-urethanes are commercially available from, for example,Lubrizol Corp under the Tecoflex™ brand. As shown in the examples below,minocycline and rifampin have been observed to be capable of rapidlyimpregnating a high polyether content (A durometer) Tecoflex™ with onlythe use of an organic solvent for the agents, such as a lower alcohol(e.g., methanol, ethanol). The solvent or lower alcohol may exert weak,reversible effects on polymer structure. This favorable combination ofagent and polymer can avoid the need for an additional penetratingagent. When penetrating agents are used, the polymer may besubstantially swollen, and mechanical benefits, such as orientation andcrystalinity, may be substantially reduced or lost upon evaporation.Further, extruded or molded shapes can swell in thickness when apenetrating agent is used, making them stiffer in certain dimensions.The use of alkalinizing agents in combination with penetrating agents toimpregnate polymeric devices may be deleterious to mechanical propertiessuch as elasticity. These combinations of agents, solvents and polymersfor impregnating preformed devices can result in a rapid, simpleimpregnating process with a reduced or minimal change to the underlyingpreformed device.

Additionally, in some embodiments, an impregnated polymer (e.g.,impregnated with M/R) can be coated with polyether polyurethane,optionally containing one or more additional antimicrobial agents. Insome embodiments, the device is coated by dipping the device into asolution of the polymer in an organic solvent or a solution comprising apermeabilizing agent and then removing the device to allow for drying.In some embodiments, the permeabilizing agent is an aliphatic ether,such as the solvent tetrahydrofuran (THF). The solution may have aconcentration of about 1-25%, 1-10%, or about 1, 2, 3, 4, 5, 6, 7, 8, 9,or 10% or any derivable range thereof. In some embodiments, the deviceis allowed to dry overnight. The device may be allowed to dry for about1-16 hours, 5-10 hours, or 5, 6, 7, 8, 9, 10 hours, or any derivablerange therein. In some embodiments, the drying occurs at roomtemperature or at an elevated temperature to speed the drying process.The drying may occur at about 25-30° C., or 25, 26, 27, 28, 29, or 30°C., or any derivable range therein.

E. Single Step Combined Antithrombogenic—Antimicrobial Coatings

Thrombogenicity of catheters can present a problem with long-termimplantations. Inhibition of thrombin activation may be used to reduceor prevent polymerization of fibrin. Heparin attachment to polymersurfaces may be used to reduce or prevent thrombin activation onintravascular polymeric devices. The processes to accomplish this aremultistep and complex because heparin is either insoluble or inactivatedby exposure to non-aqueous fluids. Heparin attachment typically involvesfirst attachment of a binding molecule or polymer to the surface,followed by activating it and exposure to aqueous heparin. Thecombination of heparin with antimicrobial agents such as chlorhexidine,gentian violet, brilliant green, minocycline and rifampin may beproblematic since the coupling chemistries are generally incompatiblewith the agents. Surprisingly, the inventors have found that a differentsmall molecule thrombin inhibitor, Argatroban, can be combined withthese antimicrobial agents in a polymeric coating using common organicsolvents compatible with M/R/CH/Gendine/Gardine such as methanol, butylacetate, THF and halogenated organics. A lower alcohol such as methanolmay be used to coat Argatroban onto a polymer or catheter surface. Insome embodiments, the Argatroban solution composition comprises about0.1-10%, 0.1-5%, or 0.1-2% Argatroban or any range derivable therein. Inaddition, further antithrombogenic protection can be accomplished byaddition of a platelet activation inhibitor. The inventors have observedthat dipyridamole can be compatible with the solvents used in thecoating and impregnating systems for M/R/CH/Gendine/Gardine, and canalso be readily combined with Argatroban and/or other antimicrobialagents in a single step coating to further reduce complications withoutintroducing additional process complexity.

III. Examples

The following examples are included to demonstrate preferred embodimentsof the invention. It should be appreciated by those of skill in the artthat the techniques disclosed in the examples which follow representtechniques discovered by the inventor to function well in the practiceof the invention, and thus can be considered to constitute preferredmodes for its practice. However, those of skill in the art should, inlight of the present disclosure, appreciate that many changes can bemade in the specific embodiments which are disclosed and still obtain alike or similar result without departing from the spirit and scope ofthe invention.

Example 1 Preparation of M/R Impregnated Polyurethane Catheter Segments

One set of Polyurethane catheter segments (4 cm) were treated withMinocycline (M) and Rifampin (R) by treatment at 45° C. in a 15%methanol/85% butyl acetate solution containing 3% Rifampin, 1.5%Minocycline and 1% sodium hydroxide. After a 1 hour treatment, thecatheter segments were air flushed and then dried overnight at 60° C.The dried catheters were triple washed in deionized water and then driedagain for 4 hours at 60° C.

A second set of catheter segments was prepared in an identical manner tothe first set except the sodium hydroxide concentration was reduced to0.33% instead of 1% and the treatment time was 2 hours instead of 1hour.

A third set of catheter segments was prepared in an identical manner toset number two except the wash steps were performed in 1% acetic acidsolution.

Example 2 Polyurethane Coating of Impregnated Polyurethane CatheterSegments

A fourth set was of catheters was prepared in an identical manner to thethird in Example 1. In addition, the surface was coated withpolyurethane by briefly dipping in a 6% aliphatic polyether-urethanesolution (Tecoflex® 93A, Lubrizol Corp) in tetrahydrofuran (THF) forthis set of catheter segments. The coated catheter segments were driedat room temperature by hanging in a chemical fume hood overnight.

Example 3 Measurement of Flex Angle to the Onset of Kinking

The 4 cm long segments were tested for onset of kinking by fixing oneend and slowly bending/rotating the other end. The onset of kinking wasnoted as the angle at which the bend point began to buckle. The anglewas measured by protractor. The results of this analysis are shown belowin Table 1.

TABLE 1 Sodium hydroxide treatment rinse Angle to onset concentrationtime medium of kinking 0% (untreated control) none 72 degrees   1% 1 hrwater 83 degrees 0.33% 2 hr water 94 degrees 0.33% 2 hr acetic acid 103degrees  0.33% (polymer coated) 2 hr acetic acid 125 degrees 

The greater the angle until the onset of kinking, then the more tolerantthe catheter segment was towards bending/flexure.

Example 4 Chlorhexidine-Minocycline-Rifampin (CH-M-R) Treated CatheterStability

4 cm long catheter segments were impregnated with CH-M-R by firstpresaturating in Chlorhexidine diacetate (4%) for 1 hour in 20% THF/80%methanol followed by treatment with 3% R, 1.5% M and 0.33% sodiumhydroxide for 2 hours at 45° C. in 15% methanol/85% butyl acetatesolution. Following drying, the segments were triple rinsed in 1% aceticacid solution and dried again. One set of samples was further coated byimmersion in a solution of 7% Tecoflex® 93A containing 3% chlorhexidinein 70% THF/30% methanol followed by retraction within a few seconds andair drying.

The samples were allowed to age at ambient temperature. Following threeweeks aging, a powder migrated to the surface of the impregnatedcatheter making it rougher and discolored. The polymer coated segmentsretained a shiny and smooth surface finish.

Example 5 Antimicrobial Impregnation of Low Durometer AliphaticPolyurethane without Penetrating or Alkalizing Agents

Tecoflex® 93A polyurethane was obtained from Lubrizol Corp. It was castinto cylindrical segments. The cylindrical segments were impregnated byexposing them to a solution of 15% Minocycline and 30% Rifampin inmethanol for 2, 5, 10, and 15 minutes at room temperature. The segmentswere dried and then cross-sectioned to determine the extent ofimpregnation. Cylindrical segments were also impregnated with Gendine byexposure to a solution of 0.1% Gentian Violet and 4% chlorhexidinediacetate in methanol at room temperature. Impregnation was performedfor 2, 5, 10, and 15 minutes. The segments were dried and thencross-sectioned to determine the extent of impregnation. Cylindricalsegments were also impregnated with Gendine by exposure to a solution of0.3% Gentian Violet and 4% chlorhexidine diacetate in methanol at roomtemperature. The segments were dried and then cross-sectioned todetermine the extent of impregnation. Segments treated with methanol andno antimicrobial agents at 25° C. exhibited slight radial swelling(about 10-20%) and returned to their original diameters on drying.

Example 6 Antimicrobial Performance of Different PolyurethanesImpregnated with Minocycline/Rifampin (M/R) without the Use ofPenetrating and Alkalizing Agents (with Only Solvent)

Impregnation of 3 different types of polyurethanes was attempted byimmersing extruded segments in a solution of 15 mg/mL Minocycline and 30mg/ml Rifampin in methanol at 20° C. for 30 minutes. Followingimpregnation, the segments were rinsed in water and then dried. Thetypes of polyurethane impregnated were low durometer aliphaticpolyetherurethane (Tecoflex® 93 A), high durometer aliphaticpolyetherurethane (Tecoflex® 55D) and low durometer aromaticpolyetherurethane (Tecothane® 95A). Controls were untreated segments ofeach of the types of polymers that were not impregnated.

Following a modified Kuhn's model of biofilm colonization [H. Hanna etal., 2006; R. Hachem et al., 2009], 1 cm long segments of uncoatedcontrol, and impregnated catheter segments were tested in triplicate forthe inhibition of biofilm formation by a clinical isolate ofAcinetobacter baumannii from our hospital. The segments were soaked for24 hours at 37° C. in donor human plasma and then in serum at 37° C. for1 week. Three individual segments of each type of catheter were thenplaced into sterile 24-well tissue culture plates containing 1 mL of5.0×10⁵ cfu/ml bacterial cells in Muller Hinton Broth and incubated for24 hours. After incubation, the bacterial inoculum was discarded andsegments washed by shaking for 30 min in 1 mL of 0.9% sterile saline.The segments were then removed with sterile sticks, placed in 5 mL of0.9% saline and sonicated for 15 minutes. After sonication, each samplewas vortexed for 5 seconds and 100 μL of sonicate liquid was seriallydiluted and plated onto Trypticase Soy Agar+5% Sheep Blood forquantitative culture. Plates were then incubated at 37° C. inverted for24 hours and counted for colony growth. Results are presented in FIG. 1.

Example 7 Reduction in Adherent Acinetobacter baumanii (Cfu/mL) toDifferent Polyurethane Substrates Impregnated with M/R Using OnlySolvent and without Penetrating or Alkalizing Agents

Only the low durometer aliphatic polyether urethane displayed a 4-logreduction in microbial attachment when no penetrating or alkalizingagents were used in the M/R treatments. High durometer aliphaticpolyether urethane and low durometer aromatic polyether urethane gave a2 log reduction or less in adherent organisms. This demonstrates thatnot all polyurethanes perform similarly when only a solvent (methanol)is utilized; hence the need to include penetrating (butyl actetate) andalkalizing agents (sodium hydroxide) in the prior art. We havesurprisingly found that durable M/R antimicrobial protection (4-logreduction in adherent organisms) could be obtained for a specificsubclass of polyurethanes (low durometer aliphatic polyether urethanes)with treatment only using a solvent and excluding the use of penetratingand/or alkalizing agents during treatment.

Example 8 Extent of Impregnation of Low Durometer Aliphatic PolyurethaneSamples with M/R and Gendine without Penetrating or Alkalizing Agents

Dried, impregnated polyurethane cylinders from example 4 were crosssectioned using a scalpel. All the M/R samples had turned reddish allthe way through the crosssection. The 2 minute Gendine exposed samplesturned light violet through the cross-sections, the samples immersed 5minutes or longer turned dark violet in color.

Samples were stretched in tension. The M/R samples treated for longerthan 5 minutes had appreciably lower tensile strengths (extended withapplication of much less force) than the 5 minute or less exposedsamples. The 2 minute, 0.1% Gendine sample required a similar force as amethanol treated control; the 5 minute and longer samples stretched moreeasily. The 0.3% Gendine samples showed a similar time extensionbehavior. The easier extension indicates plasticization of the aliphaticpolyetherurethane by the antimicrobial agents following evaporation ofthe solvent.

The surfaces of the Gendine samples were softer and tackier than thesurface of the methanol controls.

Example 9 Polyurethane Coating of Gendine Impregnated AliphaticPolyetherurethane Segments

The 5 minute 0.3% Gendine impregnated segments were further coated witha mixture of 6% Tecoflex® 93A and 3% 60D. The coating solutions furthercontained 4% chlorhexidine diacetate and 0.1% Gentian violet in 60%THF/40% methanol. The coating was performed by dipping the cylinder intothe coating solution followed by retraction within a few seconds. Thecoated and impregnated segment was dried overnight at ambienttemperature in a chemical fume hood.

Example 10 Tensile Elongation of Gendine Aliphatic PolyetherurethaneSegments

The 93A-60D blend had a less tacky surface (harder) than the 93A onlycoating solution. Extension was further measured when a 1.25 kg weightwas suspended from the end of the 93A-60D coated segments. The resultsare shown below in Table 2.

TABLE 2 Impregnation Treatment Coating % Elongation control none 76% 5minutes 0.3% none 100%  Gendine in methanol 5 minutes, 0.3%polyurethane/Gendine 83% Gendine in methanol

The coating nearly restored the original tensile properties of theGendine impregnated sample. The coated sample was less tacky and firmerthan the Gendine samples in Example 6.

Example 11 Preparation of Coating Solution Containing Argatroban

The coating solution described in Example 9 further had ArgatrobanMonohydrate dissolved at 1% concentration. A non-tacky, smooth coatingresulted on the catheter surface following immersion, retraction anddrying.

Example 12 Comparison of M/R High Durometer Aliphatic PolyurethaneCatheters Prepared with Solvent, Penetrating and Alkalizing Agents withM/R Low Durometer Aliphatic Polyurethane Catheters Prepared UsingSolvent Only

Catheter segments were prepared from low durometer polyetherurethane bythe methanol immersion method in Example 6 except impregnation was for60 minutes. M/R high durometer polyurethane catheter segments were alsoprepared by the method in U.S. Pat. Nos. 5,624,704 and 5,902,283employing penetrating agent (butyl acetate), solvent (methanol) andalkalizing agent. Controls were segments of both types of polyurethanethat were M/R treated.

Microbiological Baseline Testing: Segments were tested in triplicate forability to resist colonization by Acinetobacter baumanii. Segments wereplaced into sterile 24-well tissue culture plates containing 1 ml ofhuman donor plasma for 24 hr to simulate the binding of blood proteinsand incubated at 37° C. The plasma were then replaced with 5.0×105 cellsin Muller Hinton Broth of A. baumanii incubated for an additional 24 h.After incubation, the bacterial inoculum was discarded and segments werewashed by shaking for 30 min in 1 ml of 0.9% sterile saline. Thesegments were then removed with sterile sticks, placed in 5 ml of 0.9%saline and sonicated for 15 min. After sonication, each sample wasvortexed for 5 s and 100 μl of liquid from each segment was seriallydiluted and plated onto Trypticase Soy Agar+5% Sheep Blood forquantitative culture. Plates were then incubated at 37° C. for 24 h andcounted for colony growth.

Microbiological Durability Testing: To test the durability of prolongedinhibition of biofilm formation in a simulated physiologic environment,control and M/R catheter segments were further incubated in serum at 37°C. for 1 week and then challenged with A baumanii inoculum as describedabove. Another set was incubated for two weeks and another for 3 weeks(serum replaced weekly). A. baumanii challenges for each additional setof incubated catheter segments were performed as described above.

Quantitative A. baumanii recoveries are reported below for baseline, 1week, 2 weeks and 3 weeks. The control catheters (different polyurethanebase materials) gave nearly identical results so an average control isreported in FIG. 2 .

At 1 week, the 60 minute methanol impregnation was able to completelyprevent A. baumanii colonization demonstrating improved durability overthe 30 minute treatment in Example A. The complete prevention of A.baumanii colonization was retained through 3 weeks. Performance of theM/R catheter prepared with solvent, penetrating agent and alkalizingagent was similar through 2 weeks but breakthrough A. baumanii adherenceoccurred at week 3. The methanol (solvent only) M/R impregnation of thelow durometer aliphatic polyurethane demonstrated equivalent or superiorperformance at each time point to the M/R catheters prepared with higherdurometer polyurethane using the solvent, penetrating and alkalizingagent method described in U.S. Pat. No. 5,624,74 and U.S. Pat. No.5,902,283.

Example 13 Sandwich CH Coating on Solvent Only (Methanol) ImpregnatedM/R Catheter

Low durometer aliphatic polyurethane catheter segments were impregnatedwith M/R by immersion in a methanol solution (15 mg/ml Minocycline, 30mg/ml Rifampin) as in Example 12, rinsed and dried. A portion of the M/Rsegments were further sequentially coated with chlorhexidine diacetate(CH) as follows:

Lumen coating: Lumens of dried impregnated catheters will be coated bymixing CH dissolved in methanol into aliphatic polyurethane dissolved intetrahydrofuran. The final coating solution consist of 8 mg/ml CH, 1.5%polyurethane polymer in a mixed 30% Methanol/70% tetrahydrofuransolvent. The coating solution was injected through the catheter lumenand immediately air flushed/dried to dry and create a smooth lumenalsurface.

External coating: After lumen coating and drying, catheters were coatedexternally using a more concentrated CH solution with aliphaticpolyurethane polymers. The final external coating solution comprised 42mg/ml CH and 11% polyurethane in 30% Methanol/70% tetrahydrofuran mixedsolvent. The external coating is applied by rapidly dipping thenretracting the catheter followed by hanging to air dry overnight toleave a smooth surface finish.

Catheter segments with only the CH lumen and external coatings (no M/R)were prepared as well. Additional controls were untreated cathetersegments.

Ability of the catheters to resist colonization by clinical isolates ofMethicillin Resistant Staphylococcus aureus (MRSA) and Candida albicanswere tested using the microbiological method described in Example 12.Results for both baseline and durability are shown in FIG. 3 .

Only the M/R catheters with CH sandwich coating were able to completelyinhibit MRSA and C. albicans colonization for 3 weeks. The M/R catheterwith CH sandwich coating demonstrated superior performance to M/R aloneor CH alone at each time point.

Example 14 Gendine Sandwich Coating

Gendine low durometer aliphatic polyurethane catheter segments wereprepared as described in Example 5. A sandwich Gendine coating of thelumen and external surfaces was prepared as described in Example 13except the lumen coating solution in addition to CH also contained 0.02%Gentian Violet. The external coating solution in addition to CH alsocontained 0.1% Gentian Violet. Controls were untreated catheter segmentsand segments sandwich coated with CH only (as in example 13).Antimicrobial durability was tested as in Example 13. Results for MRSAchallenges are shown by FIG. 4 . Results for Candida albicans andCandida glabarata are presented in FIG. 5 . These results show that theGendine catheters prepared by sandwich coating is highly effective andoutperforms CH alone at each time point for each challenge organism.

Example 15 Gendine Sandwich Coated Teflon® Catheter

Teflon catheters were thoroughly cleaned with methanol and dried.Catheters were warmed to 40-50° C. Catheters were then immersed in awarm (50-60° C.) Fluoroetch solution for 2-3 minutes. Catheters wereimmediately rinsed in methanol for 15 seconds and then in hot (70° C.)deionized water for 30 seconds followed by rinsing in hot (70° C.)deionized water-acetic acid (2-5%) solution (pH 4) for 1 minute.Catheters were thoroughly dried. Catheters were coated gendinepolyurethane solution as in Example 9 with the modification that reducedGentian Violet concentrations ranging from 0.04% (400 ug/ml) to 0.01%(100 ug/ml) were used. The antimicrobial performance of the gendinecoated TEFLON catheters are shown below in FIG. 6 .

Example 16 Hydrogel Coated Catheters

The hydrogel coated catheters described in Examples 13 and 14 werefurther tested below with the following modifications.

Second Coating Step Addition

Catheters of Example 14 were spray coated with an additional surfacelayer of hydrogel poyetherurethane (Tecophilic® polyurethane, LubrizolCorp.) in THF solvent and polyvinylpyrrolidone in water-methanol.Following drying, the samples were manually tested for frictionalresistance by sliding wetted latex gloved finger tips along the cathetersurface. Hydrogel coated catheters were noticeably more lubricious thanwithout.

Single Coating Step Incorporation

The external coating of Example 13 was prepared with a blend ofaliphatic polyurethane and hydrogel polyetherurethanes (Tecophilic®polyurethane, Lubrizol Corp). Coatings were prepared with blend ratiosof 0:100, 1:99, 10:90, 25:75, 50:50, 75:25, 90:10 and 100:0 and withtotal polyurethane concentrations ranging from 5 to 11%. Followingdrying, the coatings were manually tested for frictional resistance bywetting latex gloved finger tips and sliding over the surfaces. Blendedcoatings with 10% or more hydrogel polyetherurethane were noticeablymore lubricious than the others.

External coatings as in Example 13 were prepared using a solution with2.4% CH, 2.3% Tecoflex® 60D, 1.5% Tecoflex® 93A and 1.5% Tecophilic® 93A(Formula 1) and 2.4% CH, 3% Tecoflex® 60D and 3% Tecophilic® 60D(Formula 2). Antimicrobial durability was tested against MRSA,Pseudomonas aeruginosa (PS), and Candida albicans (Ca) by the methoddescribed in Example 12. Results are shown in FIG. 7 . The Tecophilic®containing coatings with reduced CH and polymer concentrations showed noreduction in antimicrobial performance relative to the catheter ofExample 13.

Example 17 Impregnation with Minocycline-Rifampin and Chelator

Catheters were impregnated as in Example 12. For some catheters theimpregnation solution also contained the chelator calcium disodiumethylenediaminetetraacetic acid (CaEDTA) co-dissolved in methanol at aconcentration of 1.5% (M/R+CaEDTA). Catheters were tested for 1 weekanti-microbial durability against MRSA using the methods described inExample 12. Controls were catheters prepared as in Example 12. Resultsare shown below in FIG. 8 . The M/R+CaEDTA catheter demonstratedimproved antimicrobial durability over the M/R catheter.

Example 18 Sandwich Coated Minocycline-Rifampin and Chelator Catheters

Minocycline-Rifampin (M/R)+chelator (calcium ethylenediaminetetraaceticacid, “CaEDTA”) impregnated catheters were prepared as described inExample 17, and these catheters were further coated as described in inExample 13 (M/R+CaEDTA/CH sandwich) and Example 16 (M/R+CaEDTA/Formula 1and M/R+CaEDTA/Formula 2; using the single coating step incorporation).Antimicrobial durability was tested using the test as described inExample 16 (single coating step incorporation). Results are shown belowin FIG. 9 . For the M/R+CaEDTA catheters, the Tecophilic® containingcoatings with reduced chlorhexidine (CH) and polymer concentrationsshowed no reduction in antimicrobial performance relative to the CHsandwich coating of Example 13.

Example 19 Drainage Catheters

Surgical drainage catheters fabricated using Tecoflex® 93A. Some weresubsequently treated with MIR as described in Example 12. Some of thecatheters were additionally sandwich coated with chlorhexidine (CH) asdescribed in Example 13. Baseline microbiological testing was performedas in Example 12 against MRSA, PS and Ca. Results are shown below inFIG. 10 . The drainage catheters showed similar antimicrobialperformance for the M/R and M/R+CH sandwich treatments to the vascularcatheters.

All of the methods disclosed and claimed herein can be made and executedwithout undue experimentation in light of the present disclosure. Whilethe compositions and methods of this invention have been described interms of preferred embodiments, it will be apparent to those of skill inthe art that variations may be applied to the methods and in the stepsor in the sequence of steps of the method described herein withoutdeparting from the concept, spirit and scope of the invention. Morespecifically, it will be apparent that certain agents which are bothchemically and physiologically related may be substituted for the agentsdescribed herein while the same or similar results would be achieved.All such similar substitutes and modifications apparent to those skilledin the art are deemed to be within the spirit, scope and concept of theinvention as defined by the appended claims.

REFERENCES

The following references, to the extent that they provide exemplaryprocedural or other details supplementary to those set forth herein, arespecifically incorporated herein by reference.

-   U.S. Pat. No. 5,624,704-   U.S. Pat. No. 5,902,283-   R. Hachem et al. Antimicrob. Agents Chemother, 53(12): 5145-5149,    2009.-   H. Hanna et al. Antimicrob. Agents Chemother, 50(10): 3283-3288,    2006.-   He'bert et a., “Persistent Inhibition of Platelets During Continuous    Nitroglycerin Therapy Despite Hemodynamic Tolerance” Circulation,    95: 1308-1313, 1997.-   Lacoste et al., “Antithrombotic properties of transdermal    nitroglycerin in stable angina pectoris” The American Journal of    Cardiology Volume 73, Issue 15, p. 1058-1062, 1994.

1. A medical device comprising an aliphatic polyether polyurethanepolymer having a durometer of A or B wherein the polyurethane isimpregnated with minocycline and rifampin.
 2. The medical device ofclaim 1, wherein the aliphatic polyether polyurethane polymer has adurometer of A.
 3. The medical device of any one of claims 1-2, whereinthe polyurethane is coated or impregnated with a guanidium compound. 4.The medical device of claim 3, wherein the guanidium compound ischlorhexidine.
 5. The medical device of any one of claims 1-4, whereinsaid coating further comprises a dye.
 6. The medical device of claim 5,wherein the dye is gendine or gardine.
 7. The medical device of any oneof claims 1-3, wherein the polyurethane is coated with gendine, gardine,or chlorohexidine.
 8. The medical device of claim 7, wherein thepolyurethane is coated with gendine, gardine, and chlorohexidine.
 9. Themedical device of claim 3, wherein the guanidium compound ischlorhexidine.
 10. The medical device of any one of claims 1-4, furthercomprises a dye impregnated into the polyurethane.
 11. The medicaldevice of claim 10, wherein the dye is gendine or gardine.
 12. Themedical device of any one of claims 1-3, wherein the polyurethane isimpregnated with gendine, gardine, or chlorohexidine.
 13. The medicaldevice of claim 12, wherein the polyurethane is impregnated withgendine, gardine, and chlorohexidine.
 14. The medical device of claim 3,wherein the coating comprises a lower alcohol.
 15. The medical device ofany one of claims 1-14, wherein the polyurethane is impregnated with orcoated with a fatty acid.
 16. The medical device of claim 15, whereinthe fatty acid is caprylic acid (octanoic acid), caproic acid, lauricacid, or decanoic acid.
 17. The medical device of any one of claims1-16, wherein the aliphatic polyether polyurethane polymer has arepeating unit of the formula:[—O(CH₂)_(n)]_(m)—OC(O)NH—(CH₂)_(x)—NHC(O)—; wherein n=1-4, x=1-12, m is1-100; wherein the repeating unit repeats 1-250 times, and the terminusof the polymer is hydrogen.
 11. The medical device of claim 17, whereinm=1-50.
 18. The medical device of claim 17, wherein x=1-10.
 19. Themedical device of claim 17, wherein the polymer further comprises apolymer coating comprising chlorohexidine, gendine, or gardine.
 20. Themedical device of claim 19, wherein the polymer coating furthercomprises a polyurethane, a silicone, a vinyl, a fluoropolymer, anolefin, or a polymer blend or copolymer thereof.
 21. The medical deviceof claim 20, wherein the polymer coating is a polyurethane coating. 22.The medical device of claim 21, wherein the polyurethane coating is analiphatic polyether polyurethane.
 23. The medical device of claim 21,wherein the polyurethane coating has a durometer of A or D, or thecoating comprises a blend of A and D durometer aliphatic polyetherpolyurethanes.
 24. The medical device of claim 19, wherein thepolyurethane coating comprises a blend of A and D durometer aliphaticpolyether polyurethanes.
 25. The medical device of any one of claims1-24, wherein the aliphatic polyether polyurethane is comprised in acoating on the medical device.
 26. The medical device of any one ofclaims 1-24, wherein the aliphatic polyether polyurethane is notcomprised in a coating on the medical device.
 27. The medical device ofany one of claims 1-24, wherein the medical device does not comprise apenetrating or alkalizing agent.
 28. The medical device of any one ofclaims 1-27, wherein the medical device is a catheter, an endotrachealtube, a nephrostomy tube, a biliary stent, an orthopedic device, avalve, a prosthetic valve, a drainage tube, a drain, a shunt, a staple,a clip, a mesh, a film, a blood exchanging device, a port, acardiovascular device, a defibrillator, a pacemaker lead, a wirecoating, an ocular implant, an auditory implant, a cochlear implant, adental implant, a stimulator, a drug delivery depot, a filter, amembrane, a vascular access port, a stent, an envelope, a bag, a sleeve,intravenous or other tubing, a bag, a dressing, a patch, a fiber, a pin,a vascular graft, a suture, a cardiovascular suture, or an implantableprosthesis.
 29. The medical device of claim 28, wherein the medicaldevice is a catheter.
 30. The medical device of claim 29, wherein thecatheter is a vascular catheter, a urinary catheter, an intracranialcatheter, an intraspinal catheter, a peritoneal catheter, a centralnervous system catheter, a cardiovascular catheter, a drainage catheter,a soaker catheter, an aspirating catheter, an intrathecal catheter, aneural catheter, a stimulating catheter, or an epidural catheter. 31.The medical device of claim 30, wherein the catheter is a vascularcatheter.
 32. The medical device of claim 31, wherein the vascularcatheter is a central venous catheter, an arterial line, an pulmonaryartery catheter, a peripheral venous catheter, an intravenous catheter,or an intraarterial catheter.
 33. The medical device of claim 1, whereina surface of the polyurethane is coated with gendine, gardine, orchlorohexidine in a lower alkyl alcohol solvent.
 34. The medical deviceof claim 1, wherein said minocycline and rifampin have been impregnatedin the polyurethane using a solution that does not comprise apenetrating or alkalizing agent.
 35. The medical device of claim 1,wherein the medical device does not comprise a penetrating or alkalizingagent.
 36. The medical device of any one of claims 1-35, wherein thepolyurethane further comprises an additional therapeutic agent.
 37. Themedical device of claim 36, wherein the additional therapeutic agent isimpregnated in the polyurethane.
 38. The medical device of claim 36,wherein the additional therapeutic agent is coated on a surface of thepolyurethane.
 39. The medical device of claim 36, wherein thetherapeutic agent is an antimicrobial agent.
 40. The medical device ofclaim 39, wherein the antimicrobial agent is chlorhexidine, gendine, orgardine.
 41. The medical device of claim 36, wherein the additionaltherapeutic agent is a thrombin inhibitor, a platelet inhibitor, ananti-inflammatory agent, an anti-fibrotic agents, or a vasodilator. 42.The medical device of claim 41, wherein the additional therapeutic agentis argatroban, dipyridamole, a glyceryl nitrate or mercaptoethanesulfonate (MeSNA).
 43. The medical device of claim 36, wherein theadditional therapeutic agent is calcium channel blocker, or ananti-arrhythmia drug.
 44. The medical device of claim 43, wherein theadditional therapeutic agent is verapamil or thioridazine.
 45. Themedical device of any one of claims 1-44, wherein the at least a portionof the medical device is coated with a hydrogel polyetherurethane. 46.The medical device of claim 45, wherein the hydrogel polyetherurethaneis a TECOPHILIC, TECOFLEX, or a polyurethane copolymer.
 47. The medicaldevice of any one of claims 1-46, wherein the medical device comprisespolytetrafluoroethylene.
 48. The medical device of any one of claims1-46, wherein a surface of the medical device is coated or the device isimpregnated with a chelator.
 49. The medical device of claim 48, whereinthe chelator is calcium disodium EDTA.
 50. The medical device of claim49, wherein the calcium disodium EDTA is comprised in an amount of about0.01-1.5% EDTA in a coating solution.
 51. The medical device of any oneof claims 1-49, wherein the medical device is a catheter.
 52. Themedical device of claim 51, wherein the catheter is a drainage catheteror a vascular catheter.
 53. The medical device of claim 51, wherein thecatheter is impregnated or coated with chlorhexidine.
 54. The medicaldevice of any one of claims 1-53, wherein the aliphatic polyetherpolyurethane polymer is coated on the surface of the medical device. 55.A medical device comprising an aliphatic polyether polyurethane polymerhaving a durometer of A or B wherein the polyurethane is impregnatedwith chlorhexidine, gendine, or gardine.
 56. The medical device of claim55, wherein the aliphatic polyether polyurethane is coated with a secondpolymer.
 57. The medical device of claim 56, wherein the second polymeris a polyurethane.
 58. The medical device of any one of claims 55-57,wherein the aliphatic polyether polyurethane is impregnated withchlorhexidine and gardine.
 59. The medical device of any one of claims55-57, wherein the aliphatic polyether polyurethane is impregnated withchlorhexidine and gendine.
 60. The medical device of any one of claims55-57, wherein the aliphatic polyether polyurethane is impregnated withchlorhexidine, gendine, and gardine.
 61. The medical device of any oneof claims 55-60, wherein the second polymer comprises minocycline andrifampin.
 62. The medical device of claim 61, wherein the polymer is apolyurethane.
 63. The medical device of claim 61, wherein thepolyurethane is an aliphatic polyether polyurethane.
 64. The medicaldevice according to any one of claims 55-61, wherein the second polymerhas a durometer of A or D, or the coating comprises a blend of A and Ddurometer aliphatic polyether polyurethanes.
 65. The medical device ofclaim 55, wherein the polyurethane coating comprises a blend of A and Ddurometer aliphatic polyether polyurethanes.
 66. The medical device ofclaim 55, wherein the medical device is a catheter.
 67. The medicaldevice of any one of claims 55-66, wherein the at least a portion of themedical device is coated with a hydrogel polyetherurethane.
 68. Themedical device of claim 67, wherein the hydrogel polyetherurethane is aTECOPHILIC, TECOFLEX, or a polyurethane copolymer.
 69. The medicaldevice of any one of claims 55-68, wherein a surface of the medicaldevice is coated or impregnated with a chelator.
 70. The medical deviceof claim 69, wherein the chelator is calcium disodium EDTA.
 71. Themedical device of any one of claims 55-70, wherein the medical device isa catheter.
 72. The medical device of claim 71, wherein the catheter isa drainage catheter or a vascular catheter.
 73. The medical device ofclaim 71, wherein the catheter is impregnated or coated withchlorhexidine.
 74. The medical device of any one of claims 55-73,wherein the aliphatic polyether polyurethane polymer is coated on thesurface of the medical device.
 75. A medical device, comprising apolymer impregnated with minocycline and rifampin, wherein a surface ofthe polymer is coated with a polymer coating comprising a fatty acid ora guanidium compound.
 76. The medical device of claim 75, wherein thepolymer coating comprises a polyurethane, a silicone, a vinyl, afluoropolymer, an olefin, or a polymer blend or copolymer thereof. 77.The medical device of claim 75, wherein the polymer ispolytetrafluoroethylene.
 78. The medical device of claim 75, wherein thepolymer coating is a polyurethane coating.
 79. The medical device ofclaim 78, wherein the polyurethane coating has a durometer of A or D, orthe coating comprises a blend of A and D durometer aliphatic polyetherpolyurethanes.
 80. The medical device of claim 78, wherein thepolyurethane comprises chlorhexidine.
 81. The medical device of claim78, wherein the fatty acid is caprylic acid (octanoic acid), caproicacid, lauric acid, or decanoic acid.
 82. The medical device of claim 81,wherein the fatty acid is capyrlic acid.
 83. The medical device ofclaims 75-82, wherein the polymer coating further comprisesmercaptoethane sulfonate (MeSNA).
 84. The medical device of claim 83,wherein the medical device further comprises a thrombin inhibitor, aplatelet inhibitor, an anti-inflammatory agent, an anti-fibrotic agents,or a vasodilator.
 85. The medical device of claim 75, wherein themedical device further comprises a thrombin inhibitor, a plateletinhibitor, an anti-inflammatory agent, an anti-fibrotic agents, or avasodilator.
 86. The medical device of claim 75, wherein the polymer ispolyurethane, silicone, a polyvinyl chloride (PVC), a fluoropolymer, ora polyester, or a copolymer or blend thereof.
 87. The medical device ofany one of claims 75-86, wherein the at least a portion of the medicaldevice is coated with a hydrogel polyetherurethane.
 88. The medicaldevice of claim 87, wherein the hydrogel polyetherurethane is aTECOPHILIC, TECOFLEX, or a polyurethane copolymer.
 89. The medicaldevice of any one of claims 1-88, wherein the medical device comprisespolytetrafluoroethylene.
 90. The medical device of 40-50.3, wherein thepolytetrafluoroethylene is TEFLON.
 91. The medical device of any one ofclaims 1-90, wherein a surface of the medical device is coated orimpregnated with a chelator.
 92. The medical device of claim 91, whereinthe chelator is calcium disodium EDTA.
 93. The medical device of any oneof claims 1-92, wherein the medical device is a catheter.
 94. Themedical device of claim 93, wherein the catheter is a drainage catheteror a vascular catheter.
 95. The medical device of claim 93, wherein thecatheter is impregnated or coated with chlorhexidine.
 96. The medicaldevice of any one of claims 1-96, wherein the aliphatic polyetherpolyurethane polymer is coated on the surface of the medical device. 97.An antimicrobial catheter, wherein the body of the catheter comprises anA durometer aliphatic polyether polyurethane polymer, wherein thepolyurethane is impregnated either with (i) minocycline and rifampin; or(ii) chlorhexidine, gendine, or gardine.
 98. The catheter of claim 97,wherein the aliphatic polyether polyurethane polymer has a repeatingunit of the formula: [—O(CH₂)_(n)]_(m)—OC(O)NH—(CH₂)_(x)—NHC(O)—;wherein n=1-4, x=1-10, m is less than 100, m is greater than x, therepeating unit repeats 1-250 times, and the terminus of the polymer ishydrogen.
 99. The catheter of claim 98, wherein the repeating unitrepeats 1-100 times.
 100. The catheter of any one of claims 97-99,wherein the at least a portion of the medical device is coated with ahydrogel polyetherurethane.
 101. The catheter of claim 99, wherein thehydrogel polyetherurethane is a TECOPHILIC or a polyurethane copolymer.102. The catheter of any one of claims 97-101, wherein a surface of themedical device is coated or impregnated with a chelator.
 103. Thecatheter of claim 102, wherein the chelator is calcium disodium EDTA ora citrate.
 104. The catheter of claim 97-103, wherein the catheter isimpregnated or coated with chlorhexidine.
 105. The catheter of any oneof claims 97-104, wherein the aliphatic polyether polyurethane polymeris coated on the surface of the medical device.
 106. The catheteraccording to any one of claims 97-98, wherein the polyurethane furthercomprises a polyurethane coating comprising an additional therapeuticagent.
 107. The catheter of claim 106, wherein the additionaltherapeutic agent is an antimicrobial agent.
 108. The catheter of claim107, wherein the antimicrobial agent is chlorhexidine, gendine, orgardine.
 109. The catheter of claim 107, wherein the coating compriseschlorhexidine and gendine.
 110. The catheter of claim 107, wherein thecoating comprises chlorhexidine and gardine.
 111. The catheter of claim107, wherein the antimicrobial agent is minocycline or rifampin. 112.The catheter of claim 107, wherein the coating comprises minocycline andrifampin.
 113. The catheter of claim 106, wherein the additionaltherapeutic agent is a thrombin inhibitor, a platelet inhibitor, or avasodilator.
 114. The catheter of claim 113, wherein the additionaltherapeutic agent is argatroban, dipyridamole, a glyceryl nitrate or athrombin inhibitor.
 115. The catheter according to any one of claims97-114, wherein the catheter is a vascular catheter, a urinary catheter,an intracranial catheter, an intraspinal catheter, or an epiduralcatheter.
 116. The catheter of claim 115, wherein the catheter is avascular catheter.
 117. The catheter of claim 116, wherein the vascularcatheter is a central venous catheter, an arterial line, an pulmonaryartery catheter, a peripheral venous catheter, an intravenous catheter,or an intraarterial catheter.
 118. A method of catheterizationcomprising inserting a catheter of any one of claims 97-117 into asubject.
 119. The method of claim 118, wherein the subject is a mammal.120. The method of claim 119, wherein the subject is human.
 121. Amethod of producing an antimicrobial polymer, comprising: (a) contactingan aliphatic polyether polyurethane with a solution comprising a firstlower alcohol and at least one antimicrobial agent for an amount of timesufficient to impregnate the at least one antimicrobial agent in thealiphatic polyether polyurethane; wherein the solution does not containa penetrating agent or an alkalizing agent; and (b) substantially dryingthe aliphatic polyether polyurethane.
 122. The method of claim 121,wherein the at least one antimicrobial agent is minocycline andrifampin.
 123. The method of claim 121, wherein the at least oneantimicrobial agent is chlorhexidine.
 124. The method of claim 123,wherein the at least one antimicrobial agent further comprises gendineor gardine.
 125. The method of claim 121, wherein the lower alcohol is aC₁₋₆ alcohol.
 126. The method of claim 125, wherein the C₁₋₆ alcohol ismethanol, ethanol, propanol, butanol, or isopropanol.
 127. The method ofclaim 126, wherein the lower alcohol is methanol.
 128. The method ofclaim 121, wherein the solution consists of the lower alcohol.
 129. Themethod of claim 121, further comprising: (c) subsequent to step (a),coating at least a portion of a surface of the aliphatic polyetherpolyurethane with a second solution comprising: a second lower alcohol,a second organic solvent, and an additional therapeutic compound. 130.The method of claim 129, wherein said coating is applied tosubstantially all of the external surfaces of the aliphatic polyetherpolyurethane.
 131. The method of claim 129, wherein the second organicsolvent is an aliphatic ether solvent or a chlorinated solvent.
 132. Themethod of claim 131, wherein the chlorinated solvent is methylenechloride or chloroform.
 133. The method of claim 131, wherein thealiphatic ether solvent is tetrahydrofuran or diethyl ether.
 134. Themethod of claim 129, wherein the second lower alcohol is the samealcohol as the first lower alcohol.
 135. The method of claim 134,wherein the second lower alcohol is a C₁₋₆ alcohol.
 136. The method ofclaim 135, wherein the second lower alcohol is methanol, ethanol,propanol, butanol, or isopropanol.
 137. The method of claim 136, whereinthe lower alcohol is methanol.
 138. The method of claim 129, wherein thesolvent is tetrahydrofuran and the second lower alcohol is methanol.139. The method of claim 129, wherein the additional therapeuticcompound is a second antimicrobial agent.
 140. The method of claim 139,wherein the second antimicrobial agent is chlorhexidine, gendine,gardine, minocycline, or rifampin.
 141. The method of claim 129, whereinthe additional therapeutic agent is a thrombin inhibitor, a plateletinhibitor, an anti-inflammatory agent, an antifibrotic agent, or avasodilator.
 142. The method of claim 141, wherein the additionaltherapeutic agent is argatroban, or dipyridamole.
 143. The method ofclaim 129, wherein the additional therapeutic agent is calcium channelblocker or an anti-arrhythmia drug.
 144. The method of claim 143,wherein the additional therapeutic agent is verapamil or thioridazine.145. The method of claim 129, wherein said coating has a durometer of Aor D, or the coating comprises a blend of A and D durometer aliphaticpolyether-urethanes.
 146. The method of claim 121, wherein the aliphaticpolyether polyurethane has a repeating unit of the formula:[—O(CH₂)_(n)]_(m)—OC(O)NH—(CH₂)_(x)—NHC(O)—; wherein n=1-4, x=1-10, m isless than 500, m is greater than x, the repeating unit repeats 1-250times, and the terminus of the polymer is hydrogen.
 147. The method ofclaim 146, wherein m is 1-250.
 148. The method of claim 146, wherein therepeating unit repeats 1-100 times.
 149. The method of claim 146,wherein the resulting polyether polyurethane has a durometer of A or B.150. The method of claim 121, wherein the aliphatic polyether urethanepolymer is comprised in a medical device or a catheter.
 151. The methodof claim 150, wherein the aliphatic polyether urethane polymer iscomprised in an endotracheal tube, a vascular catheter, a urinarycatheter, a nephrostomy tube, a biliary stent, a peritoneal catheter, anepidural catheter, a central nervous system catheter, an intracranialcatheter, an intraspinal catheter, an epidural catheter, an orthopedicdevice, a prosthetic valve, or a medical implant.
 152. The method ofclaim 151, wherein the catheter is a vascular catheter.
 153. The methodof claim 152, wherein the vascular catheter is a central venouscatheter, an arterial line, a pulmonary artery catheter, and aperipheral venous catheter, an intraarterial catheter, or intravenous(i.v.) tubing.
 154. A method of producing an antimicrobial polymer,comprising: (a) contacting a polymer with a solution comprising a loweralcohol, minocycline, rifampin, and an alkalizing agent for an amount oftime sufficient to impregnate the minocycline and rifampin in thealiphatic polyether polyurethane; (b) exposing the polymer to aneutralizing solution comprising an alkanoic acid for an amount of timesufficient to substantially neutralize the alkalizing agent; and (c)substantially drying the polymer.
 155. The method of claim 154, whereinthe alkalizing agent is sodium hydroxide.
 156. The method of claim 154,wherein the solution further includes a penetrating agent.
 157. Themethod of claim 156, wherein the penetrating agent is ethyl acetate orbutyl acetate.
 158. The method of claim 154, wherein the polymer is apolyurethane.
 159. The method of claim 158, wherein the polyurethane isan aliphatic polyether polyurethane.
 160. The method of claim 154,wherein step (b) comprises neutralizing a majority or substantially allof the alkylating agent.
 161. The method of claim 154, wherein the loweralcohol is methanol.
 162. The method of claim 154, wherein the alkanoicacid is a C₁₋₆ alkanoic acid.
 163. The method of claim 162, wherein theC₁₋₆ alkanoic acid is acetic acid, formic acid, propionic or butyricacid.
 164. The method of claim 163, wherein the C₁₋₆ alkanoic acid isacetic acid.
 165. The method of claim 154, further comprising: (d)subsequent to step (a), coating at least a portion of a surface of thealiphatic polyether polyurethane with a second solution comprising: asecond lower alcohol, a second organic solvent, and an additionaltherapeutic compound.
 166. The method of claim 165, wherein said coatingis applied to substantially all of the external surfaces of thealiphatic polyether polyurethane.
 167. The method of claim 165, whereinthe second organic solvent is an aliphatic ether solvent or achlorinated solvent.
 168. The method of claim 167, wherein thechlorinated solvent is methylene chloride or chloroform.
 169. The methodof claim 167, wherein the aliphatic ether solvent is tetrahydrofuran ordiethyl ether.
 170. The method of claim 165, wherein the second loweralcohol is the same alcohol as the first lower alcohol.
 171. The methodof claim 165, wherein the second lower alcohol is methanol.
 172. Themethod of claim 165, wherein the solvent is tetrahydrofuran and thesecond lower alcohol is methanol.
 173. The method of claim 165, whereinthe additional therapeutic compound is an antimicrobial agent.
 174. Themethod of claim 173, wherein the antimicrobial agent is chlorhexidine,gendine, or gardine.
 175. The method of claim 165, wherein theadditional therapeutic agent is a thrombin inhibitor, a plateletinhibitor, an anti-inflammatory agent, an antifibrotic agent, or avasodilator.
 176. The method of claim 165, wherein the additionaltherapeutic agent is argatroban, or dipyridamole.
 177. The method deviceof claim 165, wherein the additional therapeutic agent is calciumchannel blocker or an anti-arrhythmia drug.
 178. The medical device ofclaim 177, wherein the additional therapeutic agent is verapamil orthioridazine.
 179. The method of claim 165, wherein said coating has adurometer of A or D, or the coating comprises a blend of A and Ddurometer aliphatic polyether-urethanes.
 180. The method of claim 154,wherein the aliphatic polyether urethane polymer is comprised in amedical device or a catheter.
 181. The method of claim 154, wherein thepolymer is comprised in an endotracheal tube, a vascular catheter, aurinary catheter, a nephrostomy tube, a biliary stent, a peritonealcatheter, an epidural catheter, a central nervous system catheter, anintracranial catheter, an intraspinal catheter, an epidural catheter, anorthopedic device, a prosthetic valve, or a medical implant.
 182. Themethod of claim 181, wherein the catheter is a vascular catheter. 183.The method of claim 182, wherein the vascular catheter is a centralvenous catheter, an arterial line, a pulmonary artery catheter, and aperipheral venous catheter, an intraarterial catheter, or intravenous(i.v.) tubing.
 184. A catheter comprising a polymer tubing, wherein thepolymer tubing is an aliphatic polyether polyurethane polymer, apolyurethane polymer coated with an aliphatic polyether polyurethanepolymer, or a polytetrafluoroethylene polymer coated with an aliphaticpolyether polyurethane polymer; wherein the polymer is coated orimpregnated with chlorhexidine, gendine, gardine, minocycline, and/orrifampin.
 185. The catheter of claim 184, further comprising a secondpolymer coating on the polymer tubing.
 186. The catheter of claim 185,wherein the second polymer coating comprises an aliphatic polyetherpolyurethane.
 187. The catheter of claim 186, wherein the coatingcomprises chlorhexidine, gendine, gardine, minocycline, and/or rifampin.188. The catheter of any one of claims 184-187, wherein the devicefurther comprises an additional therapeutic agent.